The relationship between rheumatoid arthritis and reproductive function

There is growing support for the theory that an interaction between the immune and reproductive/endocrine systems underlies the pathogenesis of autoimmune rheumatic diseases. Most of the recent evidence derives from studies of sex hormones and pregnancy in women with systemic lupus. Other than an ameliorative effect of pregnancy, little is known about reproductive factors in relation to rheumatoid arthritis. To elucidate the relationship, a population-based retrospective study was undertaken. Included were 378 female residents of Olmsted County, Minnesota diagnosed with rheumatoid arthritis between 1950 and 1982 (cases) and 325 arthritis-free, married female controls matched to the 324 married cases on birth-year, age at first marriage, and duration of Olmsted County residency. Information of reproductive factors was extracted from the medical records system maintained by the Mayo Clinic.^ Cases had lower fertility rates compared with the female population of Minnesota (rate ratio = 0.86, 95% confidence interval (CI)= 0.80-0.92). Fertility was significantly reduced even prior to the onset of rheumatoid factor positive arthritis. Restricting the comparison to married Olmsted County residents did not alter the results. Further adjustments for time not at risk of conception using survival analysis and proportional hazards modeling only intensified the fertility reduction in the married cases compared with controls. Nulligravidity was more common among cases than controls (odds ratio = 3.16, CI = 1.61-6.20). Independent of fertility, pregnancy had a protective effect against rheumatoid arthritis (odds ratio = 0.31, CI = 0.11-0.89), which was dramatically reversed in the 12 months postpartum (odds ratio = 4.67, CI = 1.50-14.47). Cases were younger at menopause than controls (p $<$ 0.01).^ Small but statistically insignificant associations were observed between rheumatoid arthritis and the following factors: increased frequency of complaints to a physician of infertility; increased frequency of spontaneous abortion, premature birth, and congenital malformations following arthritis onset; and increased prevalence of menopause at arthritis onset. Cases did not differ from controls on age at menarche, duration of pregnancy, or birth weight.^ The findings provide further support for the involvement of the reproductive/endocrine systems in the pathogenesis of autoimmune rheumatic disease. The search for biological mechanisms should be intensified. ^

Phthalate exposure among US women, NHANES 1999--2002: Relationship to serum gonadotropin levels

Phthalates are industrial chemicals used primarily as plasticizers though they and are found in a myriad of consumer goods such as children's toys, food packaging, dental sealants, cosmetics, pharmaceuticals, perfumes, and building materials. US biomonitoring data show more than 75% of the population have exposure to mono-n-butyl phthalate (MBP), mono-ethyl phthalate (MEP), mono-(2-ethyl) hexyl phthalate (MEHP), and mono-benzyl phthalate (MBZP). Reproductive toxicity from phthalate exposure in animal models has raised concerns about similar effects on fertility in humans. This dissertation research focuses on phthalate exposures in the US population and investigates the plausibility of an exposure-response relationship between phthalates and endocrine hormones essential for ovulation among US women. The objective of this research is to determine the relationship between levels of gonadotropins, follicle stimulating hormone (FSH) and leutinizing hormone (LH), and urinary phthalate monoester metabolites: MBP, MEP, MEHP, MBZP among National Health and Nutrition Examination Survey (NHANES) 1999-2002 women aged 35 to 60 years. Using biomarker data from a one-third sub-sample of NHANES participants, log transformed serum FSH and serum LH, respectively were regressed on phthalates controlling for age, body mass index, smoking, and creatinine taking into consideration the complex survey design (n=385). Models were stratified by reproductive status: reproductive (n=185), menopause transition (n=49) and post-menopausal (n=125). A decrease in FSH associated with increasing MBzP (beta=-0.094, p<0.05) was observed for all participants but no statistical association between log FSH and MBP, MEP, or MEHP was seen. A decrease in LH (beta=-0.125, p<0.05) was also observed with increasing MBzP for all participants though there was no relationship between levels of LH and MBP, MEP, or MEHP. The observed associations between FSH, LH and MBzP did not persist when stratified by reproductive status. Thus, the present study shows a change in endocrine hormones related to ovulation with increasing urinary MBzP among a representative sample of US women from 1999-2002 though this observed exposure-response relationship does not remain after stratification by reproductive status. ^

Hepatitis C and human immunodeficiency virus infections in injecting drug users in drug treatment centers in Vietnam

Background. Injecting drug users (IDUs) are at risk of infection with Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV). Independently, each of these viruses is a serious threat to health, with HIV ravaging the body’s immune system, and HCV causing cirrhosis, liver cancer and liver failure. Co-infection with HIV/HCV weakens the response to antiretroviral therapy in HIV patients. IDUs with HIV/HCV co-infection are at a 20 times higher risk of having liver-related morbidity and mortality than IDUs with HIV alone. In Vietnam, studies to ascertain the prevalence of HIV have found high rates, but little is known about their HCV status. ^ Purpose. To measure the prevalence of HCV and HIV infection and identify factors associated with these viruses among IDUs at drug treatment centers in northern Vietnam. ^ Methods. A cross-sectional study was conducted from November 2007 to February 2008 with 455 injecting drug users aged 18 to 39 years, admitted no more than two months earlier to one of four treatment centers in Northern Vietnam (Hatay Province) (response rate=95%). Participants, all of whom had completed detoxification and provided informed consent, completed a risk assessment questionnaire and had their blood drawn to test for the presence of antibody-HCV and antibody-HIV with enzyme immuno assays. Univariate and multivariable logistic regression models were utilized to explore the strength of association using HIV, HCV infections and HIV/HCV co-infection as outcomes and demographic characteristics, drug use and sexual behaviors as factors associated with these outcomes. Unadjusted and adjusted odds ratios and 95% confidence intervals were calculated. ^ Results. Among all IDU study participants, the prevalence of HCV alone was 76.9%, HIV alone was 19.8%. The prevalence of HIV/HCV co-infection was 92.2% of HIV-positive and 23.7% of HCV-positive respondents. No sexual risk behaviors for lifetime, six months or 30 days prior to admission were significantly associated with HCV or HIV infection among these IDUs. Only duration of injection drug use was independently associated with HCV and HIV infection, respectively. Longer duration was associated with higher prevalence. Nevertheless, while HCV infection among IDUs who reported being in their first year of injecting drugs were lower than longer time injectors, their rates were still substantial, 67.5%. ^ Compared with either HCV mono-infection or HIV/HCV non-infection, HIV/HCV co-infection was associated with the length of drug injection history but was not associated with sexual behaviors. Higher education was associated with a lower prevalence of HIV/HCV co-infection. When compared with HIV/HCV non-infection, current marriage was associated with a lower prevalence of HIV/HCV co-infection. ^ Conclusions. HCV was prevalent among IDUs from 18 to 39 years old at four drug treatment centers in northern Vietnam. Co-infection with HCV was predominant among HIV-positive IDUs. HCV and HIV co-infection were closely associated with the length of injection drug history. Further research regarding HCV/HIV co-infection should include non-injecting drug users to assess the magnitude of sexual risk behaviors on HIV and HCV infection. (At these treatment centers non-IDUs constituted 10-20% of the population.) High prevalence of HCV prevalence among IDUs, especially among HIV-infected IDUs, suggests that drug treatment centers serving IDUs should include not only HIV prevention education but they should also include the prevention of viral hepatitis. In addition, IDUs who are HIV-positive need to be tested for HCV to receive the best course of therapy and achieve the best response to HIV treatment. These data also suggest that because many IDUs get infected with HCV in the first year of their injection drug career, and because they also engaged in high risk sexual behaviors, outreach programs should focus on harm reduction, safer drug use and sexual practices to prevent infection among drug users who have not yet begun injecting drugs and to prevent further spread of HCV, HIV and co-infection. ^

Women physicians' specialty choices

Three hypotheses have been offered to explain the historical specialty selection by women physicians. They are: (1) women choose the specialty for which the training requirements and working conditions interfere least with their commitments to marriage and children; (2) women tend to select the more "feminine" specialties such as pediatrics and psychiatry, and to avoid the "masculine" fields such as surgery; and (3) women have been deliberately excluded from male-dominated fields such as surgery. While the above hypotheses may be true to a greater or lesser degree, none of them has been adequately tested.^ The major study hypotheses are as follows: (1) female physicians' choice of specialty is influenced by the following reasons: (a) family responsibilities; (b) sex role expectations; and (c) sex discrimination; (2) female physicians' choice of specialty is also influenced by their age and ethnicity; and (3) the primary reasons for choosing a given specialty vary by type of specialty.^ The reasons for specialty selection will be explored based on a survey of women graduates of one of the oldest medical schools in the United States, The University of Texas Medical Branch (UTMB) in Galveston, Texas (n = 930). The survey response rate was 75.3% (700 respondents).^ The results for the first study hypothesis showed that fewer than 14% of the respondents agreed that sex role expectations, sex discrimination and family responsibilities played a role in their choice of specialty. Fifty nine percent of the respondents disagreed with the idea that sex role expectations influenced specialty selection and 64% disagreed that family responsibilities had an effect on the selection of their specialty. Around half (49%) were uncertain of the influence of sex discrimination. It was concluded that sex discrimination, sex role expectations and family responsibilities did not have a major impact on specialty selection.^ With respect to the second hypothesis, age was significant in Internal Medicine, Obstetrics/Gynecology and Psychiatry. Women physicians in Internal Medicine and Obstetrics/Gynecology were significantly younger (less than 45 years old) while physicians in Psychiatry were significantly older (45 years or older) than other specialties studied.^ The third hypothesis was confirmed: the reasons for choosing a given specialty varied by specialty.^ Respondents' comments written on the survey provided insight into other possible reasons for specialty selection including exploration of the role of mentoring and job satisfaction.^ The retrospective cross-sectional study design used in this study does not adequately capture the fact that different reasons may be given for the choice of specialty at different points in time, e.g., as the time of choosing a residency program versus several years into the future.^ In conclusion, approaches that explore the range of reasons that women elect to enter and stay within a given specialty must be explored to gain richer understanding of the complex and dynamic nature of women physicians' professional lives. (Abstract shortened by UMI.) ^

THE INCIDENCE OF PELVIC ENDOMETRIOSIS IN ROCHESTER, MINNESOTA, 1970-1979

The primary objectives of the study were to measure the incidence of pelvic endometriosis among white females of reproductive age (15-49 years) in Rochester, Minnesota, during the period 1970-1979 and to determine the risk of endometriosis by age, marital status, nun status, and educational attainment in this population. An historical prospective design was used. Incident (newly diagnosed) cases were identified from community medical records, and person-years of risk in the study population were estimated from census data.^ Almost two-thirds of the incident cases had surgically verified endometriosis, while the remainder were diagnosed by clinical findings alone. Incidence rates were prepared first with histologically confirmed cases only and then with the successive inclusion of less certain cases: surgically visualized, clinically probable, and clinically possible. On this basis, overall incidence rates were 108.8 to 246.9 newly diagnosed cases per 100,000 person-years. The incidence of pelvic endometriosis was lowest for women 15-19 years of age, increased markedly through age 44, and then declined for women 45-49 years of age. A significantly greater risk of pelvic endometriosis in never married women was detected only when the numerator was limited to histologically confirmed cases. Among never married women 20-49 years of age, no significant difference in the risk of pelvic endometriosis by nun status was detected, but a trend toward a lower incidence in nuns was observed. Women with education beyond high school had a significantly higher incidence of endometriosis than women with less education.^ Cases in the four diagnostic groups differed greatly by age and marital status but were similar with respect to virtually all other characteristics, once age differences were considered. Reproductive history characteristics described included: age of menarche; history of menopause; total pregnancies; ages of first pregnancy, marriage, and sexual intercourse; years from menarche to first intercourse; years of ovulatory cycling; difficulty becoming pregnant; and delay of the first pregnancy by choice. How these characteristics of incident cases differ from those of women free of endometriosis needs to be studied in future research. ^

MEETING THE NEEDS OF HANDICAPPED CHILDREN: A STUDY OF EDUCATIONAL AND HEALTH CARE SERVICES PROVIDED TO PRE-KINDERGARTEN CHILDREN IN THE HOUSTON INDEPENDENT SCHOOL DISTRICT EARLY CHILDHOOD PROGRAM FOR THE HANDICAPPED (PARENT SATISFACTION, FUNCTIONAL STATUS, PSYCHOSOCIAL DEVELOPMENT)

The Education for All Handicapped Children Act of 1975, P.L. 94-142, created a new challenge for the nation's public school systems. During 1982-1983, a national study, called the "Collaborative Study of Children with Special Needs", was conducted in 5 metropolitan school districts to evaluate the effectiveness of education and health care services of children in kindergarten to 6th grade being provided under P.L. 94-142 programs. This dissertation (the Substudy) was undertaken to augment the findings of the Collaborative Study. The purpose of this study was to develop a database to provide descriptive information on the demographic, service and health characteristics of a small group of 3 and 4 year old handicapped children served by the Houston Independent School District (HISD) during 1982-1983.^ The study involved a stratified sample of 105 three and four year old children divided into 3 groups according to type of handicapping condition.^ The results of the study gave a clearer picture of the demographic characteristics of these Pre-K children. Specifically, sex ratio was approximately one, lower than the national norm. Family and socioeconomic characteristics were assessed.^ The study used an independence/dependence index composed of 11 items on the parent questionnaire to assess the level of functional independence of each child. An association was found between index scores and parent-reported effects of the child on family activity. Parents who said that their child's condition had affected the family's job situation, housing accomodations, vacation plans, marriage, choice of friends and social activities were also more likely to report less independence in the child. In addition, many of the Substudy children had extensive care-taking needs reflected in specific components of the index such as dressing, feeding, toileting or moving about the house.^ In general the results of the Pre-K Substudy indicate that at the early childhood level, the HISD special education program is functioning well in most areas and that parents are very satisfied with the program. (Abstract shortened with permission of author.)^

Genetic Predictors of Clinical Outcomes in Non-Small Cell Lung Cancer Patients

Lung cancer is the leading cause of cancer-related mortality in the US. Emerging evidence has shown that host genetic factors can interact with environmental exposures to influence patient susceptibility to the diseases as well as clinical outcomes, such as survival and recurrence. We aimed to identify genetic prognostic markers for non-small cell lung cancer (NSCLC), a major (85%) subtype of lung cancer, and also in other subgroups. With the fast evolution of genotyping technology, genetic association studies have went through candidate gene approach, to pathway-based approach, to the genome wide association study (GWAS). Even in the era of GWAS, pathway-based approach has its own advantages on studying cancer clinical outcomes: it is cost-effective, requiring a smaller sample size than GWAS easier to identify a validation population and explore gene-gene interactions. In the current study, we adopted pathway-based approach focusing on two critical pathways - miRNA and inflammation pathways. MicroRNAs (miRNA) post-transcriptionally regulate around 30% of human genes. Polymorphisms within miRNA processing pathways and binding sites may influence patients’ prognosis through altered gene regulation. Inflammation plays an important role in cancer initiation and progression, and also has shown to impact patients’ clinical outcomes. We first evaluated 240 single nucleotide polymorphisms (SNPs) in miRNA biogenesis genes and predicted binding sites in NSCLC patients to determine associations with clinical outcomes in early-stage (stage I and II) and late-stage (stage III and IV) lung cancer patients, respectively. First, in 535 early-stage patients, after correcting multiple comparisons, FZD4:rs713065 (hazard ratio [HR]:0.46, 95% confidence interval [CI]:0.32-0.65) showed a significant inverse association with survival in early stage surgery-only patients. SP1:rs17695156 (HR:2.22, 95% CI:1.44-3.41) and DROSHA:rs6886834 (HR:6.38, 95% CI:2.49-16.31) conferred increased risk of progression in the all patients and surgery-only populations, respectively. FAS:rs2234978 was significantly associated with improved survival in all patients (HR:0.59, 95% CI:0.44-0.77) and in the surgery plus chemotherapy populations (HR:0.19, 95% CI:0.07-0.46).. Functional genomics analysis demonstrated that this variant creates a miR-651 binding site resulting in altered miRNA regulation of FAS, providing biological plausibility for the observed association. We then analyzed these associations in 598 late-stage patients. After multiple comparison corrections, no SNPs remained significant in the late stage group, while the top SNP NAT1:rs15561 (HR=1.98, 96%CI=1.32-2.94) conferred a significantly increased risk of death in the chemotherapy subgroup. To test the hypothesis that genetic variants in the inflammation-related pathways may be associated with survival in NSCLC patients, we first conducted a three-stage study. In the discovery phase, we investigated a comprehensive panel of 11,930 inflammation-related SNPs in three independent lung cancer populations. A missense SNP (rs2071554) in HLA-DOB was significantly associated with poor survival in the discovery population (HR: 1.46, 95% CI: 1.02-2.09), internal validation population (HR: 1.51, 95% CI: 1.02-2.25), and external validation (HR: 1.52, 95% CI: 1.01-2.29) population. Rs2900420 in KLRK1 was significantly associated with a reduced risk for death in the discovery (HR: 0.76, 95% CI: 0.60-0.96) and internal validation (HR: 0.77, 95% CI: 0.61-0.99) populations, and the association reached borderline significance in the external validation population (HR: 0.80, 95% CI: 0.63-1.02). We also evaluated these inflammation-related SNPs in NSCLC patients in never smokers. Lung cancer in never smokers has been increasingly recognized as distinct disease from that in ever-smokers. A two-stage study was performed using a discovery population from MD Anderson (411 patients) and a validation population from Mayo Clinic (311 patients). Three SNPs (IL17RA:rs879576, BMP8A:rs698141, and STK:rs290229) that were significantly associated with survival were validated (pCD74:rs1056400 and CD38:rs10805347) were borderline significant (p=0.08) in the Mayo Clinic population. In the combined analysis, IL17RA:rs879576 resulted in a 40% reduction in the risk for death (p=4.1 × 10-5 [p=0.61, heterogeneity test]). We also validated a survival tree created in MD Anderson population in the Mayo Clinic population. In conclusion, our results provided strong evidence that genetic variations in specific pathways that examined (miRNA and inflammation pathways) influenced clinical outcomes in NSCLC patients, and with further functional studies, the novel loci have potential to be translated into clinical use.

A Renewed Day for Family Preservation

The philosophy and principles of family preservation have emerged in new forms over the past eight years. From the Family Preservation and Support Act of 1993 to the Adoption and Safe Families Act (ASFA) of today, the value of the family to individuals and society is clear. While family preservation "programs" per se may not be as plentiful, the principals are founding almost every array of services from children, corrections, D.D. to mental health and work with the elderly. The Administration's priorities of healthy marriage, fatherhood, incarcerated parents, and faith-based programs reflect a family-centered approach to social issues. This redefining of the village will require our renewed efforts to articulate the importance of family centered practice and policy.