The association between uterus shape and development of chronic conditions in a retrospective corhort of diethylstilbestrol-exposed women in Minnesota and Texas

Diethylstilbestrol (DES) exposed women are well known to be at increased risk of gynecologic cancers and infertility. Infertility may result from DES associated abnormalities in the shape of women's uteri, yet little research has addressed the effect of uterine abnormalities on risk of infertility and reproductive tract infection. Changes in uterine shape may also influence the risk of autoimmune disease and women's subsequent mental health. A sample of consenting women exposed in utero to hormone who were recruited into the DESAD project, underwent hysterosalpingogram (HSG) from 1978 to 1984. These women also completed a comprehensive health questionnaire in 1994 which included women's self-reports of chronic conditions. HSG data were used to categorize uterine shape abnormalities as arcuate shape, hypoplastic, wide lower segment, and constricted. Women were recruited from two of the four DESAD study sites in Houston (Baylor) and Minnesota (Mayo). All women were DES-exposed. Adjusted relative risk estimates were calculated comparing the range of abnormal uterine shaped to women with normal shaped uteri for each of the four outcomes: infertility, reproductive tract infection, autoimmune disease and depressive symptoms. Only the arcuate shape (n=80) was associated with a higher risk of infertility (relative risk [RR]= 1.53, 95% CI = 1.09, 2.15) as well as reproductive tract infection (RR= 1.74, 95% CI = 1.11, 2.73). In conclusion, DES-associated arcuate shaped uteri appeared to be associated with the higher risk of a reproductive tract infection and infertility while no other abnormal uterine shapes were associated with these two outcomes.^

In-utero exposure to chemotherapy: What are the long term effects?

There is not a large body of evidence on in-utero exposure to chemotherapy for pregnancy-associated cancers to help determine the long term effects on offspring. This study is a systematic review of long term follow-up to find evidence for adverse outcomes in exposed offspring. In order for studies to be eligible for this systematic review, they had to have a median follow up of at least 24 months with the resulting child. PubMed, Medline, and Scopus were the databases used, and we included all eligible articles, regardless of the date of publication. The search resulted in six articles meeting the eligibility requirements. The review of findings of these studies suggested that there is not enough evidence to make a determination of the risk of chemotherapy for the offspring. Exposed children in the sample of reviewed papers did have some medical conditions, but the rate and type did not differ from the non-exposed population. However, a limitation of this literature review is the very small sample size of publications on this important topic. This finding of few studies on this topic is an important result of this systematic review. More research and long term follow-up studies must be conducted to address this issue.^

Analysis of VirB4, a membrane-associated ATPase subunit essential for T -complex transport in Agrobacterium tumefaciens

Agrobacterium tumefaciens is a plant pathogen with the unique ability to export oncogenic DNA-protein complexes (T-complexes) to susceptible plant cells and cause crown gall tumors. Delivery of the T-complexes across the bacterial membranes requires eleven VirB proteins and VirD4, which are postulated to form a transmembrane transporter. This thesis examines the subcellular localization and oligomeric structure of the 87-kDa VirB4 protein, which is one of three essential ATPases proposed to energize T-complex transport and/or assembly. Results of subcellular localization studies showed that VirB4 is tightly associated with the cytoplasmic membrane, suggesting that it is a membrane-spanning protein. The membrane topology of VirB4 was determined by using a nested deletion strategy to generate random fusions between virB4 and the periplasmically-active alkaline phosphatase, $\sp\prime phoA$. Analysis of PhoA and complementary $\beta$-galactosidase reporter fusions identified two putative periplasmically-exposed regions in VirB4. A periplasmic exposure of one of these regions was further confirmed by protease susceptibility assays using A. tumefaciens spheroplasts. To gain insight into the structure of the transporter, the topological configurations of other VirB proteins were also examined. Results from hydropathy analyses, subcellular localization, protease susceptibility, and PhoA reporter fusion studies support a model that all of the VirB proteins localize at one or both of the bacterial membranes. Immunoprecipitation and Co$\sp{2+}$ affinity chromatography studies demonstrated that native VirB4 (87-kDa) and a functional N-terminally tagged HIS-VirB4 derivative (89-kDa) interact and that the interaction is independent of other VirB proteins. A $\lambda$ cI repressor fusion assay supplied further evidence for VirB4 dimer formation. A VirB4 dimerization domain was localized to the N-terminal third of the protein, as judged by: (i) transdominance of an allele that codes for this region of VirB4; (ii) co-retention of a His-tagged N-terminal truncation derivative and native VirB4 on Co$\sp{2+}$ affinity columns; and (iii) dimer formation of the N-terminal third of VirB4 fused to the cI repressor protein. Taken together, these findings are consistent with a model that VirB4 is topologically configured as an integral cytoplasmic membrane protein with two periplasmic domains and that VirB4 assembles as homodimers via an N-terminal dimerization domain. Dimer formation is postulated to be essential for stabilization of VirB4 monomers during T-complex transporter assembly. ^

Humoral immunity in tuberculin skin test anergy and its role in high-risk persons exposed to active tuberculosis.

The most common test to identify latent tuberculosis is the tuberculin skin test that detects T cell responses of delayed type hypersensitivity type IV. Since it produces false negative reactions in active tuberculosis or in high-risk persons exposed to tuberculosis patients as shown in this report, we studied antibody profiles to explain the anergy of such responses in high-risk individuals without active infection. Our results showed that humoral immunity against tuberculin, regardless of the result of the tuberculin skin test is important for protection from active tuberculosis and that the presence of high antibody titers is a more reliable indicator of infection latency suggesting that latency can be based on the levels of antibodies together with in vitro proliferation of peripheral blood mononuclear cells in the presence of the purified protein derivative. Importantly, anti-tuberculin IgG antibody levels mediate the anergy described herein, which could also prevent reactivation of disease in high-risk individuals with high antibody titers. Such anti-tuberculin IgG antibodies were also found associated with blocking and/or stimulation of in vitro cultures of PBMC with tuberculin. In this regard, future studies need to establish if immune responses to Mycobacterium tuberculosis can generate a broad spectrum of reactions either toward Th1 responses favoring stimulation by cytokines or by antibodies and those toward diminished responses by Th2 cytokines or blocking by antibodies; possibly involving mechanisms of antibody dependent protection from Mtb by different subclasses of IgG.

BRONCHOALVEOLAR LAVAGE AND GALLIUM-67 LUNG SCANNING IN THE EVALUATION OF ASBESTOS-EXPOSED INDIVIDUALS

In this study, an attempt is made to evaluate certain parameters that might indicate the beginning of a certain fibrogenic activity in the lung parenchyma, even before such changes become visible on the chest x-ray. The hypothesis is that studies such as certain bronchoalveolar immunological characteristics and Gallium-67 lung scans may be more sensitive indicators of parenchymal lung damage in response to asbestos inhalation than conventional radiographic criteria. If so, then in those cases where the criteria for the diagnosis of asbestosis lack the presence of parenchymal changes, it would be unwise to deny the diagnosis unless further investigations, such as the bronchoalveolar lavage fluid analysis and the Gallium-67 lung scan techniques, are made available.^ Four groups of individuals have been included in this study. The volunteer group showing no history of asbestos exposure with normal chest x-rays has been used as a normal healthy comparison group. The other three groups are all asbestos-exposed but differ as to their findings in the chest radiographs. One has parenchymal changes (0/1 or more, ILO Classification), the second has no parenchymal but pleural changes, and the third has neither.^ The most significant laboratory parameter for bronchoalveolar lavage, in this study, is that of Neutrophils (PMNs). All three asbestos-exposed groups showed no differences when compared with each other, while such differences were statistically significant when such groups were separately compared with the normal comparison group. A similar finding existed also when the Helper: Suppressor T-Cell ratios were compared, and found to be higher in all the asbestos-exposed groups.^ Another sensitive test is that of Gallium-67 lung scan. This was found to be positive in some patients where parenchymal changes were absent. Even in some of those who showed neither parenchymal nor pleural changes in their chest x-ray showed positive test results. Such changes indicate a state of an underlying pathogenic process that is still undetectable by conventional radiography. This highly recommends the future application of such tests for the early detection of active pulmonary disease, especially in those who show no parenchymal changes in their chest x-rays. (Abstract shortened with permission of author.) ^

REPRODUCTIVE PERFORMANCE IN THE DES-EXPOSED DAUGHTERS

This research examined the relation between prenatal exposure to diethylstilbestrol (DES) and subsequent reproductive performance in females. Although previous studies have agreed that unfavorable pregnancy outcomes (spontaneous abortions, stillbirths, ectopic pregnancies, and premature births) occur with greater frequency in the exposed as compared to unexposed women, the role of exposure to DES in-utero on subsequent fertility (pregnancy achievement) remains controversial. Also, the possibility that the reproductive dysfunction reported in exposed women might be due to familial predisposition to reproductive dysfunction rather than to DES exposure has not been examined heretofore.^ The purposes of the research were to: (1) measure the overall differences in rates of live births between exposed and unexposed women; (2) determine if infertility or early unrecognized spontaneous miscarriages (as opposed to recognized fetal death) contributes to poor reproductive performance in the exposed; and (3) determine if constitutional predisposition contributes to poor reproductive performance in exposed daughters.^ The study population comprised those participants in the National Cooperative Diethylstilbestrol Adenosis (DESAD) Project who were identified through review of prenatal records. Birth interval curves (survival analyses) were used to compare the reproductive performance of exposed daughters and unexposed women. Birth interval curves were also constructed for unexposed siblings (of exposed participants) and unexposed nonsiblings to determine the role of constitutional predisposition in the reproductive performance of exposed daughters.^ The DES-daughters, as compared to unexposed women, were found to be at a reproductive disadvantage when the overall differences in rates of live births were compared.^ When the differences in rates of live births due specifically to infertility or early unrecognized spontaneous miscarriages (as opposed to recognized fetal death) were examined, the exposed maintained the reproductive disadvantage. This analysis was suggestive but not statistically significant for the first-birth-interval and was neither suggestive nor significant in the second-birth-interval. (Abstract shortened with permission of author.) ^