Vaginal microbiome Lactobacillus crispatus is heritable among European American women.

The diversity and dominant bacterial taxa in the vagina are reported to be influenced by multiple intrinsic and extrinsic factors, including but not limited to pregnancy, contraceptive use, pathogenic states, socioeconomic status, and ancestry. However, the extent to which host genetic factors influence variation in the vaginal microbiota is unclear. We used a biometrical genetic approach to determine whether host genetic factors contribute to inter-individual differences in taxa from a sample of 332 twins who self-identified as being of African (44 pairs) or European ancestry (122 pairs). Lactobacillus crispatus, a major determinant of vaginal health, was identified as heritable among European American women (narrow-sense heritability = 34.7%, P-value = 0.018). Heritability of L. crispatus is consistent with the reduced prevalence of adverse reproductive disorders, including bacterial vaginosis and preterm birth, among women of European ancestry.

The KinFact intervention - a randomized controlled trial to increase family communication about cancer history.

BACKGROUND: Knowing family history is important for understanding cancer risk, yet communication within families is suboptimal. Providing strategies to enhance communication may be useful. METHODS: Four hundred ninety women were recruited from urban, safety-net, hospital-based primary care women's health clinics. Participants were randomized to receive the KinFact intervention or the control handout on lowering risks for breast/colon cancer and screening recommendations. Cancer family history was reviewed with all participants. The 20-minute KinFact intervention, based in communication and behavior theory, included reviewing individualized breast/colon cancer risks and an interactive presentation about cancer and communication. Study outcomes included whether participants reported collecting family history, shared cancer risk information with relatives, and the frequency of communication with relatives. Data were collected at baseline, 1, 6, and 14 months. RESULTS: Overall, intervention participants were significantly more likely to gather family cancer information at follow-up (odds ratio [OR]: 2.73; 95% confidence interval [CI]: 2.01, 3.71) and to share familial cancer information with relatives (OR: 1.85; 95% CI: 1.37, 2.48). Communication frequency (1=not at all; 4=a lot) was significantly increased at follow-up (1.67 vs. 1.54). Differences were not modified by age, race, education, or family history. However, effects were modified by pregnancy status and genetic literacy. Intervention effects for information gathering and frequency were observed for nonpregnant women but not for pregnant women. Additionally, intervention effects were observed for information gathering in women with high genetic literacy, but not in women with low genetic literacy. CONCLUSIONS: The KinFact intervention successfully promoted family communication about cancer risk. Educating women to enhance their communication skills surrounding family history may allow them to partner more effectively with their families and ultimately their providers in discussing risks and prevention.

Patient-reported hereditary breast and ovarian cancer in a primary care practice.

Identifying women appropriate for cancer genetic counseling referral depends on patient-reported family history. Understanding predictors of reporting a high-risk family is critical in ensuring compliance with current referral guidelines. Our objectives were to (1) assess prevalence of candidates for BRCA1 and BRCA2 counseling referral in a primary care setting, (2) explore associations with high-risk status and various patient (e.g., race) and family structure (e.g., number of relatives) characteristics, and (3) determine whether high-risk patients had genetic counseling and/or testing. Survey and pedigree data were collected between 2010 and 2012 for 486 Women's Health Clinic patients. Analyses in 2013 investigated perceived cancer risk and worry, family structure, and receipt of genetic counseling. We explored whether these were associated with meeting USPSTF guidelines for genetic counseling referral. Twenty-two (4.5 %) women met the criteria for BRCA referral. Only one of these women had previous genetic counseling, and one reported prior genetic testing. Older women were more likely to meet BRCA referral criteria (P < 0.001). Although perceived risk was higher among high-risk women, 27 % of high-risk women felt their breast cancer risk was "low", and 32 % felt their risk was lower than average. About one in 22 women in primary care may require genetics services for hereditary breast and ovarian cancer, but alarmingly, few actually receive these services. Also, a significant proportion do not perceive that they are at increased risk. Educational interventions may be needed for both providers and patients to increase awareness of familial risk and appropriate genetic counseling services.

Triclosan: a critical review of the experimental data and development of margins of safety for consumer products.

Triclosan (2,4,4'-trichloro-2'-hydroxy-diphenyl ether) is an antibacterial compound that has been used in consumer products for about 40 years. The tolerability and safety of triclosan has been evaluated in human volunteers with little indication of toxicity or sensitization. Although information in humans from chronic usage of personal care products is not available, triclosan has been extensively studied in laboratory animals. When evaluated in chronic oncogenicity studies in mice, rats, and hamsters, treatment-related tumors were found only in the liver of male and female mice. Application of the Human Relevance Framework suggested that these tumors arose by way of peroxisome proliferator-activated receptor alpha (PPARalpha) activation, a mode of action not considered to be relevant to humans. Consequently, a Benchmark Dose (BMDL(10)) of 47 mg/kg/day was developed based on kidney toxicity in the hamster. Estimates of the amount of intake from in the use of representative personal care products for men, women, and children were derived in two ways: (1) using known or assumed triclosan levels in various consumer products and assumed usage patterns (product-based estimates); and (2) using upper bound measured urinary triclosan levels from human volunteers (biomonitoring-based estimates) using data from the Centers for Disease Control and Prevention. For the product-based estimates, the margin of safety (MOS) for the combined exposure estimates of intake from the use of all triclosan-containing products considered were approximately 1000, 730, and 630 for men, women, and children, respectively. The MOS calculated from the biomonitoring-based estimated intakes were 5200, 6700, and 11,750 for men, women, and children, respectively. Based on these results, exposure to triclosan in consumer products is not expected to cause adverse health effects in children or adults who use these products as intended.

Expert panel report on a study of Splenda in male rats.

A recent study in rats investigated the retail sweetener product, Granulated SPLENDA No Calorie Sweetener (Splenda) (Abou-Donia et al., 2008. Splenda alters gut microflora and increases intestinal P-glycoprotein and cytochrome P-450 in male rats. J. Toxicol. Environ. Health A, 71, 1415-1429), which is composed of (by dry weight) maltodextrin ( approximately 99%) and sucralose ( approximately 1%). The investigators reported that Splenda increased body weight, decreased beneficial intestinal bacteria, and increased the expression of certain cytochrome P450 (CYP450) enzymes and the transporter protein, P-glycoprotein (P-gp), the latter of which was considered evidence that Splenda or sucralose might interfere with the absorption of nutrients and drugs. The investigators indicated that the reported changes were attributable to the sucralose present in the product tested. An Expert Panel conducted a rigorous evaluation of this study. In arriving at its conclusions, the Expert Panel considered the design and conduct of the study, its outcomes and the outcomes reported in other data available publicly. The Expert Panel found that the study was deficient in several critical areas and that its results cannot be interpreted as evidence that either Splenda, or sucralose, produced adverse effects in male rats, including effects on gastrointestinal microflora, body weight, CYP450 and P-gp activity, and nutrient and drug absorption. The study conclusions are not consistent with published literature and not supported by the data presented.

Hospitalizations of children who have fetal alcohol syndrome or incomplete fetal alcohol syndrome.

INTRODUCTION: The study describes the hospitalization rates and medical diagnoses of children with fetal alcohol syndrome (FAS) and incomplete FAS. METHODS: Two retrospective case-control studies were conducted of Northern Plains American Indian children with FAS or incomplete FAS identified from 1981-93 by using the ICD-9-CM code 760.71. Children who had FAS or incomplete FAS were compared to each other and to children who did not have FAS. RESULTS: Compared to the controls, the 43 children with FAS (Study 1) and 35 children with incomplete FAS (Study 2) were hospitalized more often with otitis media (51.2 percent OR=4.32 and 31.4 percent OR=3.02 respectively), pneumonia (46.5 percent OR=4.21 and 34.3 percent OR=2.54), fetal alcohol syndrome (32.6 percent p=.001 and 14.3 percent p=.007), dehydration (23.3 percent OR=9.29 and 17.1 percent OR=4), and anemia (11.6 percent OR=10 and 17.1 percent p=.002) respectively. Children with FAS were hospitalized more often with failure to thrive (32.6 percent p=.001) and neglect (23.3 percent OR=10.0) than children with incomplete FAS and controls. Children with FAS were hospitalized with child sexual abuse (11.6 percent OR=10.0) and feeding problems (11.6 percent p=.007), and children with incomplete FAS were hospitalized with gastroenteritis (22.9 percent OR=14.55) and bronchitis (22.9 percent OR=3.0) more than control children. CONCLUSIONS: Children with FAS or incomplete FAS had more hospitalizations and longer average length of stays than control children.

Characteristics of children whose siblings have fetal alcohol syndrome or incomplete fetal alcohol syndrome.

OBJECTIVE: To describe the clinical features of American Indian children born just before and just after a sibling with fetal alcohol syndrome or incomplete fetal alcohol syndrome. METHODS: Two retrospective case-control studies were conducted of Northern Plains American Indian children with fetal alcohol syndrome or incomplete fetal alcohol syndrome identified from 1981 to 1993 by using International Classification of Diseases, Ninth Revision, Clinical Modification code 760.71. RESULTS: Compared with the controls, the 39 siblings born just before children with fetal alcohol syndrome (study 1) and 30 siblings born just before children with incomplete fetal alcohol syndrome (study 2) had more facial dysmorphology (23.1% and 16.7%, respectively), growth delay (38.5% and 10.0%), and central nervous system impairment (48.7% and 33.3%). The 20 siblings born just after children with fetal alcohol syndrome (study 1) and 22 siblings born just after children with incomplete fetal alcohol syndrome (study 2) had more facial dysmorphology (20.0% and 9.1%, respectively), growth delay (45.0% and 22.7%), and central nervous system impairment (50.0% and 31.8%) than the control siblings. CONCLUSIONS: The "before" siblings had characteristics of fetal alcohol syndrome that could have predicted that the next child was at risk for fetal alcohol syndrome. The "after" siblings had better outcomes than the previous siblings with fetal alcohol syndrome, a finding that was associated with a decrease in maternal alcohol consumption during the after-sibling pregnancy.

Mammography screening after risk-tailored messages: the women improving screening through education and risk assessment (WISER) randomized, controlled trial.

AIMS: A randomized trial investigated the impact of risk-tailored messages on mammography in diverse women in the Virginia Commonwealth University Health System's gynecology clinics. METHODS: From 2003 to 2005, 899 patients > or =40 years of age were randomized to receive risk-tailored information or general information about breast health. Multiple logistic regression analyses summarize their breast health practices at 18 months. RESULTS: At baseline, 576 (64%) women reported having a mammogram in the past year. At 18-month follow-up, mammography rates were 72.6% in the intervention group and 74.2% in the control group (N.S.). Women (n = 123) who reported worrying about breast cancer "often" or "all the time" had significantly higher mammography rates with the intervention (85.0%) vs. the controls (63.5%). No significant differences existed in clinical breast examination, self-examination, or mammography intentions between the two study arms. However, intervention women with lower education reported significantly fewer clinical breast examinations at follow-up. CONCLUSIONS: The brief intervention with a risk-tailored message did not have a significant effect overall on screening at 18 months. However, among those who worried, mammography rates in the intervention group were higher. Individual characteristics, such as worry about breast cancer and education status, may impact interventions to improve breast cancer prevention practices.

Duration of an intervention's impact on perceived breast cancer risk.

This study explored risk perceptions after breast cancer risk appraisal. The study involved a randomized trial of Women's Health clinic patients (>or= 40 years old). Primary outcome was perceived breast cancer risk at baseline, 1 month, 6 months, and 18 months. Perceived breast cancer risks were higher than actual calculated risks at baseline. At baseline, 45% reported moderate/strong risk and 43% reported lower-than-average risk; 53% said that their risk was lower than 15%. Mean perceived lifetime risk was 31 out of 100. Throughout follow-up, the treatment group reported lower risks by all measures, as compared to controls. However, for African American women, perceived risk "out of 100 women" did not change. A brief health risk appraisal tends to lower breast cancer risk perceptions for at least 18 months, but the impact may vary by race/ethnicity. These findings could affect health behaviors, such as annual mammograms, which are influenced by perceived risk.

The impact of family history of breast cancer and cancer death on women's mammography practices and beliefs.

PURPOSE: To summarize the impact of a family history of breast cancer on mammography practices and beliefs. METHOD: Survey data concerning breast health practices and beliefs were utilized for a cross-sectional analysis. Participants were 899 racially diverse nonpregnant women 40 years and older without breast cancer. The impact of various aspects of cancer family history on mammography, perceived barriers to and benefits of screening, and perceived breast cancer risk was assessed. RESULTS: More women with a first-degree relative with breast cancer reported a mammogram within the past year and rated their breast cancer risk higher. Death of a first-degree relative impacted the belief that breast cancer can be cured with early detection. Degree of relatedness of affected relative impacted mammography practice and risk perceptions. CONCLUSION: Family history of breast cancer impacted mammography adherence, beliefs about outcomes with early detection, and risk perceptions. Breast cancer death in a family may be a better predictor of beliefs about breast cancer detection and cure than family history of cancer alone. These findings have implications for how screening recommendations and risk information are communicated to patients with different familial cancer experiences.

Alcohol use, injuries, and prenatal visits during three successive pregnancies among American Indian women on the Northern Plains who have children with fetal alcohol syndrome or incomplete fetal alcohol syndrome.

INTRODUCTION: The purpose of the study was to compare three sequential pregnancies of American Indian women who have children with FAS or children with incomplete FAS with women who did not have children with FAS. METHODS: Two retrospective case-control studies were conducted of Northern Plains American Indian children with fetal alcohol syndrome (FAS) (Study 1) or incomplete FAS (Study 2) in 1981-1993. Three successive pregnancies ending in live births of 43 case mothers who had children with FAS, and 35 case mothers who had children with incomplete FAS were compared to the pregnancies of 86 and 70 control mothers who did not have children with FAS, respectively, in the two studies. Prenatal records were abstracted for the index child (child with FAS or incomplete FAS) and siblings born just before and just after the index child, and comparable prenatal records for the controls. RESULTS: Compared to the controls, significantly more case mothers used alcohol before and after all three pregnancies and during pregnancy with the before sibling and the index child. Mothers who had children with FAS reduced their alcohol use during the pregnancy following the birth of the index child. All Study 1 case mothers (100%) and 60% of Study 2 case mothers used alcohol during the pregnancy with the index child compared to 20 and 9% of respective control mothers. More study 1 case mothers experienced unintentional injuries (OR 9.50) and intentional injuries during the index pregnancy (OR 9.33) than the control mothers. Most case mothers began prenatal care in the second trimester. CONCLUSIONS: Alcohol use was documented before, during and after each of the three pregnancies. Women of child-bearing age should be screened for alcohol use whenever they present for medical services. Mothers who had a child with FAS decreased their alcohol consumption with the next pregnancy, a finding that supports the importance of prenatal screening throughout pregnancy. Women who receive medical care for injuries should be screened for alcohol use and referred for appropriate treatment. Protective custody, case management and treatment services need to be readily available for women who use alcohol.

Characteristics of grandmothers who have grandchildren with fetal alcohol syndrome or incomplete fetal alcohol syndrome.

INTRODUCTION: Characteristics of Northern Plains American Indian maternal grandmothers who had grandchildren with fetal alcohol syndrome (FAS) or incomplete FAS are described to more effectively prevent fetal FAS and alcohol use during pregnancy. METHODS: Study 1 had 27 maternal grandmothers who had grandchildren with FAS and Study 2 had 18 grandmothers with grandchildren who had incomplete FAS (cases) which were compared with 119 maternal grandmothers who had grandchildren without FAS (controls). The grandchildren were born between 1981 and 1993 on the Northern Plains. Medical records were manually reviewed for each case and control grandmother. Data were analyzed using Mantel-Haenszel chi square. RESULTS: Study 1 case grandmothers were more likely to experience medical problems (70.4%) including trauma (48.1%) and injuries (51.9%) than the controls. Most of the Study 1 and 2 case grandmothers (92.6% and 77.8%, respectively) had alcohol use documented in their medical records compared to less than half of the control grandmothers. Seven (15.6%) of the case grandmothers had more than one grandchild in either Study 1 or Study 2. CONCLUSION: Maternal grandmothers who had grandchildren with FAS had significantly higher rates of alcohol use and alcohol-related medical problems than control grandmothers. Antenatal care providers should screen pregnant women for alcohol use at their first visit. The provider needs to ask the women who are using alcohol about their mothers' use of alcohol to provide appropriate care and counseling for the women and prevent FAS.

Recruiting diverse patients to a breast cancer risk communication trial--waiting rooms can improve access.

Low participation among underserved populations in health research constrains progress in public health practices. From 2003 to 2005, Women's Health Clinic patients at the VCU Health System were recruited to a trial investigating breast cancer risk communication. In secondary analyses, we examined dimensions of the recruitment of these diverse women. The sample characteristics (age, insurance, race and previous mammograms) were compared to the overall clinic. Of recruitment attempts for eligible women, 45% consented; of those who declined, the top cited reasons were lack of time (40%) and lack of interest (18%). Of 899 participants, 35% qualified for the indigent care program, compared to 31% of the overall clinic (P<0.001). Forty-five percent of participants were African American, compared to 54% of overall clinic patients (P<0.001). Participants were younger (50 vs. 53 years, P<0.001) than the overall clinic population. Nonrepresentative enrollment of patients in clinical trials is common and could lead to suboptimal applicability of findings. Although there were statistically significant race and age differences between the study sample and the overall population, we demonstrate that waiting room recruitment can engage diverse women in a clinical trial and cancer risk communication.

Tiered toxicity testing: evaluation of toxicity-based decision triggers for human health hazard characterization.

A set of biologically-based toxicity testing decision triggers was developed and analyzed within a tiered testing and decision-making framework for evaluating potential human health hazards and risks associated with chemical exposures. The proposed three-tiered toxicity testing approach starts from a base set of toxicity studies (acute toxicity, in vitro genetic toxicity, in vitro cytogenetics, repeat dose/subchronic toxicity, developmental toxicity, reproductive toxicity) and then uses the toxicity triggers to identify which specific additional tests are needed to adequately characterize a substance's hazard potential. The toxicity triggers were initially evaluated using published information for eight chemicals, representing diverse classes. A retrospective validation study was then conducted using seven chemicals which had completed the USEPA's Voluntary Children's Chemical Evaluation Program (VCCEP). The toxicity triggers were shown to identify appropriate higher tier tests and to be reasonably predictive of the results expected in higher tiered tests. Employing these toxicity triggers within a tiered testing framework could lead to a reduction in the number of laboratory animals without diminishing the degree of scientific certainty necessary for hazard evaluations. The toxicity triggers appear to be suitable for identifying which specific endpoints and tests warrant further evaluation, and which do not, and for documenting the scientific basis for such decisions.

Spontaneous renal tubular hyperplastic and neoplastic lesions in three Sprague-Dawley rats from a 90-day toxicity study.

Multiple renal tubular cell adenomas and atypical tubular hyperplasia were diagnosed in 2 high-dose and 1 mid-dose female Sprague-Dawley (Crl:CD (SD)IGS BR) rats from a 90-day toxicity study of an amino acid found in green tea. The tumors were bilateral multicentric adenomas accompanied by atypical foci of renal tubular hyperplasia in both kidneys of the 3 animals. Toxic tubular changes that typically accompany renal carcinogenesis were not seen in any of the other animals of the study, suggesting rather, an underlying germline mutation of a tumor suppressor gene in these three rats. The histological appearance of these tumors and short latency was reminiscent of the spontaneous lesions reported to arise in Sprague-Dawley rats in the Nihon rat model. Nihon rats develop kidney tumors as a result of a spontaneous mutation in the rat homologue of the Birt-Hogg-Dubé gene (Bhd). Frozen samples of liver from two tumor-bearing rats were assayed for germline alterations in the Bhd gene. The entire coding region (exons 3-13) of the Bhd gene was sequenced, and a guanine (nt106G) to adenine (nt106A) polymorphism was detected resulting in a glycine to arginine (G36R) substitution in both tumor-bearing animals. In the study animals, the frequency of the A-allele (adenine) was determined to be 27% (19/70). Interestingly, rats obtained from two other sources (n = 17) only carried the nt106G-allele, consistent with the published rat sequence for this gene. Genetic fingerprinting of microsatellite loci indicated that the rats had a shared genetic background. Laser capture microdissection (LCM) of the tumor cells demonstrated a loss of heterozygosity in the Bhd gene in neoplastic cells of one of the two animals. Taken together, these data suggest that the tumors observed in these animals arose spontaneously as a result of a shared genetic susceptibility leading to the development of renal tubular neoplasms.

Framework for use of toxicity screening tools in context-based decision-making.

One of the principal applications of toxicology data is to inform risk assessments and support risk management decisions that are protective of human health. Ideally, a risk assessor would have available all of the relevant information on (a) the toxicity profile of the agent of interest; (b) its interactions with living systems; and (c) the known or projected exposure scenarios: to whom, how much, by which route(s), and how often. In practice, however, complete information is seldom available. Nonetheless, decisions still must be made. Screening-level assays and tools can provide support for many aspects of the risk assessment process, as long as the limitations of the tools are understood and to the extent that the added uncertainty the tools introduce into the process can be characterized and managed. Use of these tools for decision-making may be an end in itself for risk assessment and decision-making or a preliminary step to more extensive data collection and evaluation before assessments are undertaken or completed and risk management decisions made. This paper describes a framework for the application of screening tools for human health decision-making, although with some modest modification, it could be made applicable to environmental settings as well. The framework consists of problem formulation, development of a screening strategy based on an assessment of critical data needs, and a data analysis phase that employs weight-of-evidence criteria and uncertainty analyses, and leads to context-based decisions. Criteria for determining the appropriate screening tool(s) have been identified. The choice and use of the tool(s) will depend on the question and the level of uncertainty that may be appropriate for the context in which the decision is being made. The framework is iterative, in that users may refine the question(s) as they proceed. Several case studies illustrate how the framework may be used effectively to address specific questions for any endpoint of toxicity.

Lack of oral embryotoxicity/teratogenicity with D-ribose in Wistar rats.

The present oral embryotoxicity/teratogenicity study of d-Ribose (DR) was conducted in female rats; 28 rats/group were exposed via the diet to 0, 5, 10, or 20% DR (0.0, 4.25, 7.94, 9.91g/kg body weight/day), from day 0 of gestation until Caesarian section and maternal sacrifice on day 21. All animals survived to the end of the study. Fecundity index, gestation index, pre-implantation loss, post-implantation loss, and sex ratio were all unaffected by treatment with DR. External observations of fetuses and placentas were unremarkable across the study groups. Mean fetal and placental weights, across all viable fetuses, did not differ significantly between treated and control groups. Observations of visceral malformations, anomalies, and variations were unremarkable and did not differ between treated and control groups. In summary, administration of DR to pregnant rats at concentrations up to 20% of the diet resulted in no significant adverse effects on the developing embryo/fetus at doses that were not otherwise a severe metabolic stress on the dam. A No Observed Adverse Effect Level (NOAEL) for teratogenicity could be seen at a concentration of 5% DR in the diet, corresponding to an average daily intake of DR of between 3.64 and 4.61g/kg body weight/day.