Dimethyl sulfoxide stimulates the AhR-Jdp2 axis to control ROS accumulation in mouse embryonic fibroblasts.

The aryl hydrocarbon receptor (AhR) is a ligand-binding protein that responds to environmental aromatic hydrocarbons and stimulates the transcription of downstream phase I enzyme-related genes by binding the cis element of dioxin-responsive elements (DREs)/xenobiotic-responsive elements. Dimethyl sulfoxide (DMSO) is a well-known organic solvent that is often used to dissolve phase I reagents in toxicology and oxidative stress research experiments. In the current study, we discovered that 0.1% DMSO significantly induced the activation of the AhR promoter via DREs and produced reactive oxygen species, which induced apoptosis in mouse embryonic fibroblasts (MEFs). Moreover, Jun dimerization protein 2 (Jdp2) was found to be required for activation of the AhR promoter in response to DMSO. Coimmunoprecipitation and chromatin immunoprecipitation studies demonstrated that the phase I-dependent transcription factors, AhR and the AhR nuclear translocator, and phase II-dependent transcription factors such as nuclear factor (erythroid-derived 2)-like 2 (Nrf2) integrated into DRE sites together with Jdp2 to form an activation complex to increase AhR promoter activity in response to DMSO in MEFs. Our findings provide evidence for the functional role of Jdp2 in controlling the AhR gene via Nrf2 and provide insights into how Jdp2 contributes to the regulation of ROS production and the cell spreading and apoptosis produced by the ligand DMSO in MEFs.

Risk factors for women with gestational diabetes mellitus developing type 2 diabetes and the impact on children's health.

AIM: The study aimed to explore the risk factors for progression to type 2 diabetes in women with gestational diabetes mellitus and the long-term impact of gestational diabetes mellitus on the health of their children. BACKGROUND: The occurrence of gestational diabetes mellitus in women is the strongest predictor of the development of type 2 diabetes in the future. DESIGN: A non-concurrent cohort and case-control study design and the guidelines for STROBE checklist were used for the study. METHODS: We reviewed medical records for the time period from the archives of the hospitals. The short-listed women and their children were invited to participate in a 'Women with gestational diabetes mellitus' research activity from November 2012-February 2016. Blood tests, physiological indicators and demographic questionnaires were applied for data collection. RESULTS: A total of 57 women and 57 children participated in the research activity. The risk factors for progression of gestational diabetes mellitus to type 2 diabetes included education level and the 1-h blood glucose level for the antepartum 100-g oral glucose tolerance test and the 2-h blood glucose level for the postpartum 75-g oral glucose tolerance test. However, these risk factors did not have a significant impact on the body mass index and body fat of the women's children. CONCLUSION: Healthcare providers should adopt a breadth of health education strategies to remind women with gestational diabetes mellitus to be aware of certain risk factors, and to urge them and their children to return for regular follow-up visits. RELEVANCE TO CLINICAL PRACTICE: Identification of the risk factors developing type 2 diabetes can make healthcare units incorporate the postpartum follow-up of gestational diabetes mellitus into their standard protocol and case managers continue to follow-up and manage the health of the women and that of their children to reduce adverse health of them.

Safe sexual behaviors intention among female youth: The construction on extended theory of planned behavior.

AIM: To examine female youth's intentions for safe sex with the relationship partners based on the extended theory of planned behaviour (TPB) model and explore the direct and indirect impact of parent-child communication about sex, peer interaction related to sexual issues, and exposure to sexually explicit materials on female youth's safe sexual behaviour intentions. DESIGN: A non-experimental, cross-sectional research design. METHODS: A convenience sampling was employed for data collection and 731 female youth aged 15-24 years old were recruited in 2013-2014. An anonymous, self-report structured questionnaire was used as a research instrument to collect participants' basic information and measure the internal and additional variables in the extended TPB model. RESULTS: The extended TPB model explained 42-45% of the total variance. Perceived behavioural control (PBC) and subjective norms had a positive effect on female youth's intentions for contraceptive use, condom use, and dual use with relationship partner; PBC was found to have the greatest influence. Among the additional variables in the extended TPB model, more parent-child communication about sex was found to lead to more positive dual use intentions. More peer interaction related to sexual issues was found to lead to less dual use intentions. CONCLUSIONS: To improve female youth's sexual health, the priorities are to reinforce their PBC and subjective norms and enhance parent-child communication about sex. Future efforts should strengthen sex education in families and schools and shape a social environment that facilitates safe sex. IMPACT: The extended TPB model can successfully predict female youth's safe sexual behaviour intentions. Empowering female youth to establish a sense of subjectivity and awareness of being a mature individual with physical autonomy, is importance for their sexual health.

Effects of insulin resistance on the association between the circulating retinol-binding protein 4 level and clustering of pediatric cardiometabolic risk factors.

OBJECTIVES: Retinol-binding protein 4 (RBP4) and insulin resistance (IR) are clinical parameters associated with cardiometabolic diseases. The mediating and modifying roles of IR on children's susceptibility to cardiometabolic disorders are undetermined. This study investigated the mediating and modifying effects of the homeostatic model assessment of IR (HOMA-IR) on the relationship between the serum RBP4 level and clustering of pediatric cardiometabolic risk factors. METHODS: We assessed the diet, physical activity, cardiometabolic risk factors, and clinical parameters of 272 randomly selected adolescents from a large-scale cross-sectional study (n = 2727). Two HOMA-IRs (HOMA1-IR and HOMA2-IR) were used to evaluate the designated effects. RESULTS: Levels of serum RBP4 positively correlated with the levels of the 2 HOMA-based-IRs, and HOMA-IR correlated to all components of pediatric metabolic syndrome (MetS), the number of abnormal components, and a body-weight-weighted principal component score extracted from 12 cardiometabolic risk factors. Increased RBP4 levels had positive effects on waist circumference (WC), triglyceride, and the number of abnormal MetS components (0.310 cm, 1.384 µg/dL, and 0.021 item elevations, respectively), and the HOMA-IRs explained 17.7% to 21.9%, 11.8% to 27.6%, and 23.8% to 25.0% of these effects. The association of WC and the number of abnormal MetS components with the serum RBP4 level was enhanced by higher HOMA-IR (ß for interaction, 0.13 and 0.01 for HOMA1-IR, and 0.32 and 0.02 for HOMA2-IR, respectively). CONCLUSIONS: HOMA-IR is associated with the circulating RBP4 level and cardiometabolic risk factors in adolescents. Pediatric HOMA-IR may have mediating and modifying effects on the positive correlations between RBP4 and the clustering of MetS components.

Fructose-Rich Beverage Intake and Central Adiposity, Uric Acid, and Pediatric Insulin Resistance.

OBJECTIVE: To determine the association between sugar-sweetened beverage (SSB) consumption with biomarkers of insulin resistance (IR) and investigate whether/how this relates to obesity and serum uric acid in adolescents. STUDY DESIGN: Adolescents (n = 1454, aged 12-16 years) were assessed in a study conducted to monitor Multilevel Risk Profiles for Adolescent Metabolic Syndrome in Taiwan. Detailed information about demographics, diet, physical, anthropometric, and clinical variables was collected. An original homeostatic model assessment of IR (HOMA1-IR), updated nonlinear homeostatic model assessment of IR (HOMA2-IR) model, and several IR markers were measured. RESULTS: Adolescents who consumed a greater amount of SSBs were more likely to have elevated fasting serum insulin, HOMA1-IR, and HOMA2-IR (P for trends, ≤.028). Compared with SSB nondrinkers, those with >350 mL/d intake of heavy high-fructose corn syrup-containing SSBs had a 0.52 and 0.30 higher multivariate-adjusted HOMA1-IR and HOMA2-IR, respectively. Waist circumference and serum uric acid were correspondingly found to explain 25.4% and 23.6%, as well as 23.2% and 20.6%, of the increases in the 2 IR markers. Both the elevations of HOMA1-IR and HOMA2-IR for high-fructose corn syrup-rich SSB intake were strengthened among obese adolescents (P for interaction, ≤.033). CONCLUSIONS: Fructose-rich SSB intake is associated with elevated levels of IR, and this relationship may be partially mediated by central adiposity and serum uric acid. Obesity may modify the effect of this type of SSB consumption in intensifying the elevation of IR in adolescents.

Predictors of Hyperglycemic Women's Perinatal Health Status.

BACKGROUND: Hyperglycemic women face dramatic physiological and psychosocial changes during the perinatal period; however, studies examining hyperglycemic women's health are few, and limited to cross-sectional designs. PURPOSE: This study aimed to examine changes in hyperglycemic women's stress, social support, depression, and health status from pregnancy to 1 year postpartum, and to identify factors predicting hyperglycemic women's perinatal health. METHODS: Ninety-nine participants with positive results in a 50-g glucose challenge test were recruited in a medical center in southern Taiwan. A repeated measures study was conducted; measurements were made at 28 weeks of pregnancy, and 1 week, 6 weeks, 6 months, and 1 year after childbirth. The Social Support Scale, the Perceived Stress Scale, the Taiwanese Depression Questionnaire, and the Chinese Health Questionnaire were used. RESULTS: Compared with hyperglycemic women's depression at 28 weeks of pregnancy, significant decreases in mean depression scores were found at 1 week and 1 year postpartum. Hyperglycemic women's health status improved at 6 months and 1 year postpartum. Depression significantly predicted hyperglycemic women's perinatal health status. LINKING EVIDENCE TO ACTION: Stress and depression are associated with perinatal health status in hyperglycemic women. Healthcare providers should more closely assess stress and depression levels in hyperglycemic women from pregnancy to 1 year postpartum. Interventions promoting the psychological well-being of hyperglycemic women are required.

Risk evaluation for the development of cervical intraepithelial neoplasia: development and validation of risk-scoring schemes.

Cervical cancer screening guidelines do not comprehensively define what constitutes high risk. This study developed and validated simple risk-scoring schemes to improve Papanicolaou smear screening for women at high risk. Four cumulative risk score (CRS) schemes were derived respectively for the development of cervical intraepithelial neoplasia grade 1 (CIN1) and grade 2 or worse (CIN2+) using community-based case-control data (n = 1523). By calculating the area under the receiver operating characteristic (AU-ROC) curve, these schemes were validated in a Papanicolaou smear follow-up cohort (n = 967) and a hospital-based cytology screening population (n = 217). A high DNA load of high-risk human papillomavirus (HR-HPV) was the main predictor for CIN1 and CIN2+, although age, married status combined with the number of sexual partners, active and passive smoking and age at sexual debut also affected associated lesions. In the training set, only the HPV-testing-contained CIN2+ CRS scheme presented an excellent discrimination for identifying CIN2+ (AU-ROC = 0.866). Using a CRS cutoff value of 4 to identify CIN2+, the sensitivity and specificity of predicting CIN2+ for the 3- and 5-year follow-ups were 100% and 90.8%, and 83.3% and 90.4%, respectively, in the validation cohort. In the hospital-based validation population, the CRS scheme showed comparable discrimination for CIN2+ detection (sensitivity 88.2% and specificity 84.6%). Women with CRS ≥ 4 had a 5.4% and 9.1% of 3- and 5-year cumulative incidence, respectively, and a 40.5-fold hazard ratio of developing CIN2+. In conclusion, combined with HR-HPV testing and verified risk factors, a simple CRS scheme could effectively improve the implementation of CIN2+ screening.

Toona sinensis leaf extract has antinociceptive effect comparable with non-steroidal anti-inflammatory agents in mouse writhing test.

BACKGROUND: The antinociceptive effect of an aqueous extract from the leaves of Toona sinensis (TS, [A. Juss., M. Roem.]) was studied using the writhing test in mice. METHODS: Different extraction fractions from TS leaf extracts (TSL1 to TSL5) were administered orally 1 h before intraperitoneal injection of acetic acid. RESULTS: After treatment with TSL1, TSL2, TSL3, TSL4, and TSL5 at a dose of 1 g/kg, the respective writhing responses were 39.9% (P < 0.001), 19.9% (P < 0.05), 11.7% (P = 0.052), 8.1% (P = 0.188), and 11.4% (P = 0.057) lower than the control group. Mice treated with TSL1 at 1 g/kg (39.9%, P < 0.001), 0.3 g/kg (38.0%, P < 0.001), 0.1 g/kg (46.9%, P < 0.001), and 0.03 g/kg (31.1%, P < 0.001) had significantly lower writhing responses compared with control mice. A time-course experiment was performed, which involved oral administration of TSL1 (0.1 g/kg) at 0, 0.5, 1, 2, and 6 h before acetic acid intraperitoneal injection. The most effective dose of TSL1 was 0.1 g/kg orally, with the effect beginning 30 min before treatment and persisting until 6 h. CONCLUSIONS: This study showed that TS has anti-visceral pain properties comparable with those of rofecoxib (a cyclooxygenase-2 inhibitor) and diclofenac, which suggests promise for the treatment of intractable visceral pain in humans.

HPV knowledge and factors associated with intention to use condoms for reducing HPV infection risk among adolescent women in Taiwan.

Human papillomavirus (HPV) is a frequent cause of sexually transmitted infection worldwide, and has a key role in the etiology of cervical cancer. Young people are the most vulnerable age group for acquiring HPV infection, but this particular age group in Taiwan knows little about it. This study investigated Taiwanese adolescent women's knowledge of HPV and factors associated with intention to use condoms for reducing HPV-related diseases among adolescent women. A descriptive cross-sectional design was used, and a convenience sample of 384 adolescent women aged 15 to 16 years in Southern Taiwan was recruited. Data were collected using a self-administered questionnaire and analyzed with descriptive statistics, t-test or ANOVA, and multiple regression analysis. Only 26.6% of the participants were aware of HPV. The percentage of correct answers for knowledge about HPV was 35.4%. Factors associated with intention to use condoms for HPV prevention were discussion of sexual issues, attitude, subjective norm, perceived behavioral control, and HPV knowledge. These variables accounted for 55.8% of the variance in scores for intention to use condoms for HPV prevention. These findings could be used in future HPV prevention education and campaigns. Future intervention programs might be particularly focused on insufficient HPV knowledge among adolescent females.

Postpartum fatigue, baby-care activities, and maternal-infant attachment of vaginal and cesarean births following rooming-in.

AIM: This study compares women's postpartum fatigue, baby-care activities, and maternal-infant attachment following vaginal and cesarean births in rooming-in settings. BACKGROUND: Postpartum women admitted to baby-friendly hospitals are asked to stay with their babies 24 hours a day and to breastfeed on demand regardless of the type of childbirth. METHODS: The study used a descriptive cross-sectional study design. A total of 120 postpartum women were recruited from two accredited baby-friendly hospitals in southern Taiwan. Three structured questionnaires were used to collect data, on which an analysis of covariance was conducted. RESULTS: Women who experienced a cesarean birth had higher postpartum fatigue scores than women who had given birth vaginally. Higher postpartum fatigue scores were correlated with greater difficulty in baby-care activities, which in turn resulted in weaker maternal-infant attachment as measured in the first 2 to 3 days postpartum. CONCLUSIONS: Hospitals should implement rooming-in in a more flexible way by taking women's postpartum fatigue and physical functioning into consideration.

Assessing sugar-sweetened beverage consumption in early pregnancy using a substance abuse framework.

Sugar-sweetened beverages (SSB) are previously reported to jeopardize maternal fetal health, most well-known for gestational diabetes, childhood obesity, and cognitive impairment. Although warnings and diet recommendations urge pregnant women to consume less SSB, there is no noticeable difference in their behavior. How and why reproductive women change their SSB consumption patterns were not investigated previously. Our study aims to investigate beverage consumption patterns and how these patterns change in pregnancy in the context of substance use disorder (SUD). We invited all pregnant women visiting the clinic to answer a structured 20-min questionnaire every trimester during the regular antennal visit. At the end of the study, 337 pregnant women aged over 20 participated. A total of 301 responses entered for final analysis, with a response rate of 89.3%. Our finding showed those with high DSM-5-TR scores reduced SSB intake after becoming pregnant, while those with mild or low DSM-5-TR scores increased SSB intake after becoming pregnant. The top 3 factors related to their SSB consumption were "use despite of known health hazard (n = 133)", "increased desire to drink (n = 88)", and "excessive time spent on seeking SSB (n = 85)". The least reported factors were in the domains of social impairment (ranging from n = 3 to n = 26), pharmacologic effects (i.e., tolerance (n = 24) and withdrawal (n = 70). When participants reduced SSB consumption after becoming pregnant, their choice of beverages largely shifted to sugarless beverage but not much plain water. The result provided new insights in deciphering pregnant women's psychomotor factors for SSB intake, which served as useful references for making clinical or even public health recommendations.

Traffic air pollution and risk of death from ovarian cancer in Taiwan: fine particulate matter (PM2.5) as a proxy marker.

The relationship between mortality attributed to ovarian cancer and exposure to ambient air pollutants was examined using an ecological design. The study areas consisted of 61 municipalities in Taiwan. Air quality data for recorded concentrations of fine particulate matter (PM2.5) from study municipalities for 2006-2009 were obtained as a marker of traffic emissions. These were used as a proxy for polycyclic aromatic hydrocarbons (PAH) exposure. Age-standardized mortality rates for ovarian cancer were calculated for the study municipalities for the years 1999-2008. A weighted multiple regression model was employed to calculate the adjusted risk ratio (RR) in relation to PM2.5 levels. After adjusting for urbanization level and fertility rate, the adjusted RR values (95% confidence interval [CI]) for ovarian cancer were 1.2 (1.02-1.41) for the municipalities with PM2.5 levels between 30.48 µg/m3 and 39.41 µg/m3 and 1.2 (1.03-1.39) for the municipalities with PM2.5 levels between 39.48 µg/m3 and 51.1 µg/m3, compared to the municipalities with PM2.5 levels less than 30.39 µg/m3. Results showed that individuals who resided in municipalities with higher levels of PM2.5, a proxy measure of PAH, were at an increased risk of death from ovarian cancer compared to those subjects living in municipalities with the lowest PM2.5. The findings of this study warrant further investigation into the role of exposure to air pollutants in the etiology of ovarian cancer development.

Prenatal predictors for father-infant attachment after childbirth.

AIMS AND OBJECTIVES: This study aims to assess expectant fathers' social support, marital intimacy and health status during the third trimester of their partners' pregnancies. Further, we investigate the predictors of father-infant attachment after childbirth. BACKGROUND: Becoming a father is a transition. Research has focused more on mothers than on fathers, even though the philosophy of the maternal care system is about providing family-centred care. The psychological status of first-time fathers and the attachment they have to their infants have received little attention in the research. DESIGN: A repeated measures study design. METHODS: A total of 195 first-time fathers were recruited during the third trimester of their partners' pregnancies. During that time, they completed the Social Support Scale, the Marital Intimacy Scale and the Chinese Health Questionnaire. After childbirth, they completed the Paternal Attachment Inventory during the one-week postpartum period. RESULTS: The fathers who perceived more marital intimacy and support from their partners were more attached to their infants. Moreover, marital intimacy and partner support were important predictors for father-infant attachment. CONCLUSIONS: Future research is warranted to determine the prenatal predictors of father-infant attachment for high-risk families. RELEVANCE TO CLINICAL PRACTICE: The philosophy of maternal care is family oriented; for health professionals, pregnancy is an important time to provide information and counsel couples. Interventions should not only target the health and well-being of expectant mothers but should also actively invite fathers to participate in prenatal care with their partners to facilitate marital intimacy and father-infant attachment.

Antiosteoporosis effects of a marine antimicrobial peptide pardaxin via regulation of the osteogenesis pathway.

Antimicrobial peptides (AMPs) are known to play an important role in natural immunity. Moreover, the diverse biological activities of AMPs showed great potency in treating many diseases. Thus, in this study, we used an AMP, that is, pardaxin, from a marine fish (Pardachirus marmoratus), which has been reported to possess antibacterial and antitumor activities. We first investigated the mechanisms of pardaxin in promoting osteogenic differentiation in vitro and in vivo. As per our data, it was determined that pardaxin could stimulate bone morphogenetic protein-2 (BMP-2) and downstream cascade. The activation of BMP-2 could further induce the phosphorylation of Akt and extracellular signal-regulated kinase (ERK). Additionally, the activation of p-Akt and p-ERK could prompt the elevation and translocation of runt-related transcription factor 2 (runx-2), which is associated with osteoblast differentiation. The translocation of runx-2 initiated transcription and translation of osteogenesis-related markers, including alkaline phosphatase (ALP), osterix, and osteocalcin. Pardaxin significantly facilitated preosteoblast cells in mineralization and reversed dexamethasone- (DM-) induced zebrafish bone formation deficiency by activating the osteogenesis pathway. Therefore, we suggest that pardaxin could be a possible candidate for osteoporosis treatment and a promising therapeutic agent.

Cryptocaryone Promotes ROS-Dependent Antiproliferation and Apoptosis in Ovarian Cancer Cells.

Cryptocaryone (CPC) is a bioactive dihydrochalcone derived from Cryptocarya plants, and its antiproliferation was rarely reported, especially for ovarian cancer (OVCA). This study aimed to examine the regulation ability and mechanism of CPC on three histotypes of OVCA cells (SKOV3, TOV-21G, and TOV-112D). In a 24 h MTS assay, CPC showed antiproliferation effects to OVCA cells, i.e., IC50 values 1.5, 3, and 9.5 µM for TOV-21G, SKOV3, and TOV-112D cells. TOV-21G and SKOV3 cells showed hypersensitivity to CPC when applied for exposure time and concentration experiments. For biological processes, CPC stimulated the generation of reactive oxygen species and mitochondrial superoxide and promoted mitochondrial membrane potential dysfunction in TOV-21G and SKOV3 cells. Apoptosis was detected in OVCA cells through subG1 accumulation and annexin V staining. Apoptosis signaling such as caspase 3/7 activities, cleaved poly (ADP-ribose) polymerase, and caspase 3 expressions were upregulated by CPC. Specifically, the intrinsic and extrinsic apoptotic caspase 9 and caspase 8 were overexpressed in OVCA cells following CPC treatment. Moreover, CPC also stimulated DNA damages in terms of γH2AX expression and increased γH2AX foci. CPC also induced 8-hydroxy-2'-deoxyguanosine DNA damages. These CPC-associated principal biological processes were validated to be oxidative stress-dependent by N-acetylcysteine. In conclusion, CPC is a potential anti-OVCA natural product showing oxidative stress-dependent antiproliferation, apoptosis, and DNA damaging functions.

Generation of Human Stomach Cancer iPSC-Derived Organoids Induced by Helicobacter pylori Infection and Their Application to Gastric Cancer Research.

There is considerable cellular diversity in the human stomach, which has helped to clarify cell plasticity in normal development and tumorigenesis. Thus, the stomach is an interesting model for understanding cellular plasticity and for developing prospective anticancer therapeutic agents. However, many questions remain regarding the development of cancers in vivo and in vitro in two- or three-dimensional (2D/3D) cultures, as well as the role of Helicobacter pylori (H. p.) infection. Here, we focus on the characteristics of cancer stem cells and their derived 3D organoids in culture, including the formation of stem cell niches. We define the conditions required for such organoid culture in vitro and examine the ability of such models for testing the use of anticancer agents. We also summarize the signaling cascades and the specific markers of stomach-cancer-derived organoids induced by H. p. infection, and their stem cell niches.

Stem Cell Biomarkers and Tumorigenesis in Gastric Cancer.

Stomach cancer has a high mortality, which is partially caused by an absence of suitable biomarkers to allow detection of the initiation stages of cancer progression. Thus, identification of critical biomarkers associated with gastric cancer (GC) is required to advance its clinical diagnoses and treatment. Recent studies using tracing models for lineage analysis of GC stem cells indicate that the cell fate decision of the gastric stem cells might be an important issue for stem cell plasticity. They include leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5+), Cholecystokinin receptor 2 (Cckr2+), and axis inhibition protein 2 (Axin2+) as the stem cell markers in the antrum, Trefoil Factor 2 (TFF2+), Mist1+ stem cells, and Troy+ chief cells in the corpus. By contrast, Estrogen receptor 1 (eR1), Leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1), SRY (sex determining region Y)-box 2 (Sox2), and B lymphoma Mo-MLV insertion region 1 homolog (Bmi1) are rich in both the antrum and corpus regions. These markers might help to identify the cell-lineage identity and analyze the plasticity of each stem cell population. Thus, identification of marker genes for the development of GC and its environment is critical for the clinical application of cancer stem cells in the prevention of stomach cancers.

Parity, age at first birth, and risk of death from liver cancer: Evidence from a cohort in Taiwan.

BACKGROUND AND AIM: The present study was undertaken to examine whether there is an association between parity and age at first birth and risk of liver cancer. METHODS: The study cohort consisted of 1,292,462 women who had a first and singleton childbirth between 1 January 1978 and 31 December 1987. We tracked each woman from the time of their first childbirth to 31 December 2007, and their vital status was ascertained by linking records with the computerized mortality database. Cox proportional hazard regression models were used to estimate the relative risks (RR) of death from liver cancer associated with parity and age at first birth. RESULTS: There were 826 liver cancer deaths during 32,464,186.58 person-years of follow-up. The mortality rate of liver cancer was 2.54 cases per 100,000 person-years. The adjusted RR was 1.59 (95% confidence interval [CI] = 1.36-1.86) for women who gave birth between 26 and 30, 2.41 (95% CI = 1.81-3.20) for women who gave birth between 31 and 35, and 6.26 (95% CI = 4.27-9.19) for women who gave birth after 35 years of age, respectively, when compared with women who gave birth at less than 25 years of age. The adjusted RR was 0.72 (95% CI = 0.59-0.87) for women who had two to three children, and 0.63 (95% CI = 0.47-0.84) for women with four or more births, respectively, when compared with women who had given birth to only one child. CONCLUSIONS: The present study suggests that reproductive factors (parity and early age at first birth) may confer a protective effect on the risk of liver cancer.