Male microchimerism in females: a quantitative study of twin pedigrees to investigate mechanisms.

STUDY QUESTION: Does having a male co-twin, older brothers, or sons lead to an increased probability of persistent male microchimerism in female members of twin pedigrees? SUMMARY ANSWER: The presence of a male co-twin did not increase risk of male microchimerism and the prevalence of male microchimerism was not explained by having male offspring or by having an older brother. WHAT IS KNOWN ALREADY: Microchimerism describes the presence of cells within an organism that originate from another zygote and is commonly described as resulting from pregnancy in placental mammals. It is associated with diseases with a female predilection including autoimmune diseases and pregnancy-related complications. However, microchimerism also occurs in nulliparous women; signifying gaps in the understanding of risk factors contributing to persistent microchimerism and the origin of the minor cell population. STUDY DESIGN, SIZE, DURATION: This cross-sectional study composed of 446 adult female participants of the Netherlands Twin Register (NTR). PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants included in the study were female monozygotic (MZ) twins, female dizygotic same-sex twins and females of dizygotic opposite-sex twin pairs, along with the mothers and sisters of these twins. Peripheral blood samples collected from adult female participants underwent DNA extraction and were biobanked prior to the study. To detect the presence of male-origin microchimerism, DNA samples were tested for the relative quantity of male specific Y chromosome gene DYS14 compared to a common ß-globin gene using a highly sensitive quantitative PCR assay. MAIN RESULTS AND THE ROLE OF CHANCE: We observed a large number of women (26.9%) having detectable male microchimerism in their peripheral blood samples. The presence of a male co-twin did not increase risk of male microchimerism (odds ratio (OR) = 1.23: SE 0.40, P = 0.61) and the prevalence of male microchimerism was not explained by having male offspring (OR 0.90: SE 0.19, P = 0.63) or by having an older brother (OR = 1.46: SE 0.32, P = 0.09). The resemblance (correlation) for the presence of microchimerism was similar (P = 0.66) in MZ pairs (0.27; SE 0.37) and in first-degree relatives (0.091; SE 0.092). However, age had a positive relationship with the presence of male microchimerism (P = 0.02). LIMITATIONS, REASONS FOR CAUTION: After stratifying for variables of interest, some participant groups resulted in a low numbers of subjects. We investigated microchimerism in peripheral blood due to the proposed mechanism of cell acquisition via transplacental blood exchange; however, this does not represent global chimerism in the individual and microchimerism may localize to numerous other tissues. WIDER IMPLICATIONS OF THE FINDINGS: Immune regulation during pregnancy is known to mitigate allosensitization and support tolerance to non-inherited antigens found on donor cells. While unable to identify a specific source that promotes microchimerism prevalence within pedigrees, this study points to the underlying complexities of natural microchimerism in the general population. These findings support previous studies which have identified the presence of male microchimerism among women with no history of pregnancy, suggesting alternative sources of microchimerism. The association of detectable male microchimerism with age is suggestive of additional factors including time, molecular characteristics and environment playing a critical role in the prevalence of persistent microchimerism. The present study necessitates investigation into the molecular underpinnings of natural chimerism to provide insight into women's health, transplant medicine and immunology. STUDY FUNDING/COMPETING INTEREST(S): This work is funded by Royal Netherlands Academy of Science Professor Award (PAH/6635 to D.I.B.); The Netherlands Organisation for Health Research and Development (ZonMw)-Genotype/phenotype database for behavior genetic and genetic epidemiological studies (ZonMw 911-09-032); Biobanking and Biomolecular Research Infrastructure (BBMRI-NL, 184.021.007; 184.033.111); The Netherlands Organisation for Scientific Research (NWO)-Netherlands Twin Registry Repository (NWO-Groot 480-15-001/674); the National Institutes of Health-The Rutgers University Cell and DNA Repository cooperative agreement (NIMH U24 MH068457-06), Grand Opportunity grants Integration of genomics and transcriptomics in normal twins and major depression (NIMH 1RC2 MH089951-01), and Developmental trajectories of psychopathology (NIMH 1RC2 MH089995); and European Research Council-Genetics of Mental Illness (ERC 230374). C.B.L. declares a competing interest as editor-in-chief of Human Reproduction and his department receives unrestricted research grants from Ferring, Merck and Guerbet. All remaining authors have no conflict-of-interest to declare in regards to this work. TRIAL REGISTRATION NUMBER: N/A.

Feasibility study for performing uterus transplantation in the Netherlands.

STUDY QUESTION: Is it feasible to perform uterus transplantations (UTx) in a tertiary centre in the Netherlands? SUMMARY ANSWER: Considering all ethical principles, surgical risks and financial aspects, we have concluded that at this time, it is not feasible to establish the UTx procedure at our hospital. WHAT IS KNOWN ALREADY: UTx is a promising treatment for absolute uterine factor infertility. It is currently being investigated within several clinical trials worldwide and has resulted in the live birth of 19 children so far. Most UTx procedures are performed in women with the Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, a congenital disorder characterized by absence of the uterus. In the Netherlands, the only possible option for these women for having children is adoption or surrogacy. STUDY DESIGN SIZE DURATION: We performed a feasibility study to search for ethical, medical and financial support for performing UTx at the Amsterdam UMC, location VUmc. PARTICIPANTS/MATERIALS SETTING METHODS: For this feasibility study, we created a special interest group, including gynaecologists, transplant surgeons, researchers and a financial advisor. Also, in collaboration with the patients' association for women with MRKH, a questionnaire study was performed to research the decision-making in possible recipients. In this paper, we present an overview of current practices and literature on UTx and discuss the results of our feasibility study. MAIN RESULTS AND THE ROLE OF CHANCE: A high level of interest from the possible recipients became apparent from our questionnaire amongst women with MRKH. The majority (64.8%) positively considered UTx with a live donor, with 69.6% having a potential donor available. However, this 'non-life-saving transplantation' requires careful balancing of risks and benefits. The UTx procedure includes two complex surgeries and unknown consequences for the unborn child. The costs for one UTx are calculated to be around €100 000 and will not be compensated by medical insurance. The Clinical Ethics Committee places great emphasis on the principle of non-maleficence and the 'fair distribution of health services'. LIMITATIONS REASONS FOR CAUTION: In the Netherlands, alternatives for having children are available and future collaboration with experienced foreign clinics that offer the procedure is a possibility not yet investigated. WIDER IMPLICATIONS OF THE FINDINGS: The final assessment of this feasibility study is that that there are not enough grounds to support this procedure at our hospital at this point in time. We will closely follow the developments and will re-evaluate the feasibility in the future. STUDY FUNDING/COMPETING INTERESTS: This feasibility study was funded by the VU Medical Center (Innovation grant 2017). No conflicts of interest have been reported relevant to the subject of all authors. TRIAL REGISTRATION NUMBER: n.a.

Low prevalence of male microchimerism in women with Mayer-Rokitansky-Küster-Hauser syndrome.

STUDY QUESTION: Is there an increased prevalence of male microchimerism in women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, as evidence of fetal exposure to blood and anti-Müllerian hormone (AMH) from a (vanished) male co-twin resulting in regression of the Müllerian duct derivatives? SUMMARY ANSWER: Predominant absence of male microchimerism in adult women with MRKH syndrome does not support our hypothesis that intrauterine blood exchange with a (vanished) male co-twin is the pathophysiological mechanism. WHAT IS KNOWN ALREADY: The etiology of MRKH is unclear. Research on the phenotype analogous condition in cattle (freemartinism) has yielded the hypothesis that Müllerian duct development is inhibited by exposure to AMH in utero. In cattle, the male co-twin has been identified as the source for AMH, which is transferred via placental blood exchange. In human twins, a similar exchange of cellular material has been documented by detection of chimerism, but it is unknown whether this has clinical consequences. STUDY DESIGN, SIZE, DURATION: An observational case-control study was performed to compare the presence of male microchimerism in women with MRKH syndrome and control women. Through recruitment via the Dutch patients' association of women with MRKH (comprising 300 members who were informed by email or regular mail), we enrolled 96 patients between January 2017 and July 2017. The control group consisted of 100 women who reported never having been pregnant. PARTICIPANTS/MATERIALS, SETTING, METHODS: After written informed consent, peripheral blood samples were obtained by venipuncture, and genomic DNA was extracted. Male microchimerism was detected by Y-chromosome-specific real-time quantitative PCR, with use of DYS14 marker. Possible other sources for microchimerism, for example older brothers, were evaluated using questionnaire data. MAIN RESULTS AND THE ROLE OF CHANCE: The final analysis included 194 women: 95 women with MRKH syndrome with a mean age of 40.9 years and 99 control women with a mean age of 30.2 years. In total, 54 women (56.8%) were identified as having typical MRKH syndrome, and 41 women (43.2%) were identified as having atypical MRKH syndrome (when extra-genital malformations were present). The prevalence of male microchimerism was significantly higher in the control group than in the MRKH group (17.2% versus 5.3%, P = 0.009). After correcting for age, women in the control group were 5.8 times more likely to have male microchimerism (odds ratio 5.84 (CI 1.59-21.47), P = 0.008). The mean concentration of male microchimerism in the positive samples was 56.0 male genome equivalent per 1 000 000 cells. The prevalence of male microchimerism was similar in women with typical MRKH syndrome and atypical MRKH syndrome (5.6% versus 4.9%, P = 0.884). There were no differences between women with or without microchimerism in occurrence of alternative sources of XY cells, such as older brothers, previous blood transfusion, or history of sexual intercourse. LIMITATIONS, REASON FOR CAUTION: We are not able to draw definitive conclusions regarding the occurrence of AMH exchange during embryologic development in women with MRKH syndrome. Our subject population includes all adult women and therefore is reliant on long-term prevalence of microchimerism. Moreover, we have only tested blood, and, theoretically, the cells may have grafted anywhere in the body during development. It must also be considered that the exchange of AMH may occur without the transfusion of XY cells and therefore cannot be discovered by chimerism detection. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to test the theory that freemartinism causes the MRKH syndrome in humans. The study aimed to test the presence of male microchimerism in women with MRKH syndrome as a reflection of early fetal exposure to blood and AMH from a male (vanished) co-twin. We found that male microchimerism was only present in 5.3% of the women with MRKH syndrome, a significantly lower percentage than in the control group (17.2%). Our results do not provide evidence for an increased male microchimerism in adult women with MRKH as a product of intrauterine blood exchange. However, the significant difference in favor of the control group is of interest to the ongoing discussion on microchimeric cell transfer and the possible sources of XY cells. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: Dutch trial register, NTR5961.

Magnetic resonance cholangiopancreatography (MRCP) of intraductal papillary-mucinous neoplasm (IPMN) of the pancreas: case report.

The intraductal papillary-mucinous neoplasm (IPMN) is the rarest of the cystic pancreatic tumors. Endoscopic retrograde cholangiopancreatography (ERCP) is currently the gold standard for evaluating IPMN's and can demonstrate dilatation of the main duct or side branches, mural nodules, filling defects, and communication between the tumor and the main pancreatic duct. Recent literature has shown that MRCP may be more sensitive and specific in the diagnosis of IPMN In this case report, we present a patient with IPMN of the pancreas where MRCP was superior to ERCP in characterizing the tumor.

Lung cancer in New South Wales: current trends and the influence of age and sex.

OBJECTIVE: To examine the effects of time, sex and age at diagnosis on lung cancer incidence rates and the distribution of the histological types of lung cancer in New South Wales. DESIGN AND SETTING: Retrospective analysis of data from the NSW Cancer Registry and Australian Bureau of Statistics population data for NSW for 1985-1995. MAIN OUTCOME MEASURES: Trends in lung cancer incidence rates between 1985 and 1995 for men and women aged over 30 years; changes in incidence rates within age groups; and incidence rates of histological subtypes relative to sex and age. RESULTS: The incidence of lung cancer in men aged 40-80 years fell, while that in women aged over 65 rose. Rates were stable in younger women and older men. Incidence rates in men aged 40-60 years fell by 40%-60%. Were it not for the reduction in incidence rates in men between 1985 and 1995, the number of male lung cancer cases in 1995 would have been greater by 389 (95% CI, 362-415). In women, increasing incidence rates were responsible for an extra 242 cases (95% CI, 232-253) in 1995. Adenocarcinoma comprised a greater percentage of lung cancer cases in younger people, while squamous-cell carcinoma increases steadily with age in both men and women. Women with lung cancer are less likely to have squamous-cell carcinoma (25% for women v. 40% for men) and therefore more likely than men to have adenocarcinoma (35% of new female cases v. 26% for men) or small-cell lung cancer (24% v. 19%). CONCLUSIONS: Increased smoking cessation has seen a halving of lung cancer rates in middle-aged men. Whether this represents delayed or prevented cases is uncertain. The distribution of histological subtypes of lung cancer in women is different from that in men, and it is not clear whether this difference is hormone-dependent or related to historical patterns of smoking.

Incomplete reporting of men's fertility in the United States and Britain: a research note.

We evaluate men's retrospective fertility histories from the British Household Panel Survey and the U.S. Panel Study of Income Dynamics (PSID). Further, we analyze the PSID men's panel-updated fertility histories for their possible superiority over retrospective collection. One third to one half of men's nonmarital births and births within previous marriages are missed in estimates from retrospective histories. Differential survey underrepresentation of previously married men compared with previously married women accounts for a substantial proportion of the deficits in previous-marriage fertility. More recent retrospective histories and panel-updated fertility histories improve reporting completeness, primarily by reducing the proportion of marital births from unions that are no longer intact at the survey date.

The impact of child support on cognitive outcomes of young children.

We use the National Longitudinal Survey of Youth-Child data to address three questions. First, does the receipt of child support have beneficial effects for children with absent fathers apart from increasing income? Second, do the effects of child support differ when child-support awards and payments are made cooperatively as opposed to being court ordered? Third, are any positive effects of child support solely a product of unmeasured differences among fathers and families? Controlling for the socioeconomic characteristics of the child and family, we find some evidence that receipt of child support has a positive impact on children's cognitive test scores over and above its contribution to total income. However, the effects vary by test, by race, and by reason for father's absence. Our results also indicate that the distinction between cooperative and noncooperative awards is important. Finally, our instrumental variables estimates show that the effects of child support persist after we control for unobserved characteristics of fathers and families.

Economic incentives for financial and residential independence.

In this paper we examine the impact of the resource of children and of their parents on the children's transition to residential and financial independence. Previous studies of this transition focused primarily on the impact of family structure and parent-child relationships on the decision to leave home, but much less in known about the role of economic factors in the transition to independence. Using data from the Panel Study of Income Dynamics (PSID) for the period 1968-1988, we estimate discrete-hazard models of the probability of achieving residential and financial independence. We find that the child's wage opportunities and the parents' income are important determinants of establishing independence. The effect of parental income changes with the child's age. We also find some evidence that federal tax policy influences the decision to become independent, although the magnitude of this effect is quite small.

Responses of female labor supply and fertility to the demographic cycle.

PIP: A model is proposed in which women change the timing of childbearing and duration of time not working following childbearing in order to mitigate any adverse effects of the demographic cycle upon their lifetime wages. The authors explore the reduced-form empirical implications of their model and estimate the importance of the responses using data from three cohorts of the National Longitudinal Surveys of Labor Market Experience which include data on women born during 1918-64. Hazard rate estimates of the timing of the first birth and the return to work following that birth indicate that women who were born during the upswing of the demographic cycle begin childbearing earlier and return to work more quickly than do women who were born during the downswing of the demographic cycle. These results suggest that when responding to the demographic cycle, the cohort choice effect is more important than the opportunity cost effect.^ieng

The Easterlin effect.

"The Easterlin effect posits cyclical changes in demographic and social behavior as the result of fluctuations in birth rates and cohort size during the post-World War II period.... The Easterlin effect has generated a large literature in the several decades since it was first proposed. Our review of the empirical studies notes the diversity of support across behaviors, time periods, and nations.... Our review emphasizes both the contingent nature of the Easterlin effect and the way in which conditions have changed in recent decades to reduce the salience of cohort size for social and demographic behavior."

Enforcing divorce settlements: evidence from child support compliance and award modifications.

This paper uses an implicit contracting framework to understand the dynamic nature of divorce settlements and to analyze the determinants of noncompliance with child support awards. In addition to the standard economic variables that affect the noncustodial parent's (NCP's) ability to pay child support, our approach focuses on factors that may affect the NCP's desire to pay, such as the ongoing relationship between the two parents and between the NCP and the children. We also examine the "state-contingent" nature of child support payments and explore the factors that lead to modifications in child support agreements. Using a longitudinal data set collected by the Stanford Child Custody Project, the empirical analysis provides documentation that compliance by noncustodial fathers can vary substantially from month to month. In addition, we find that even within a short period after divorce, a substantial minority of parents agree to make informal modifications to their divorce settlement in response to changes in economic circumstances and in custodial arrangements.

Retained intrahepatic stones. Use of the U tube during repeated nonoperative stone extractions.

Of 355 patients undergoing nonoperative extraction procedures for retained bile duct stones, 61 patients had intrahepatic calculi. In seven of these patients with multiple intrahepatic stones and two of them with additional hepatic duct strictures.trahepatic stones, a U tube was placed. Insertion of a U tube is particularly useful if multiple sittings are required for intrahepatic stone removal. The U tube can be inserted postoperatively and permits ease of operation from two sides, particulary if stricture dilation is required before stone removal. With the use of the U tube, inadvertent removal has not occurred and patients are able to work and shower between extraction procedures. Indwelling U tubes are readily replaced over a guide wire. This technique was used with good success and for long periods of time in seven patients, all with multiple intrahepatic stones and two of them with additional hepatic duct strictures.

Enzymatic dissolution of phytobezoars.

A review of phytobezoars is presented, emphasizing medical treatment using enzymatic dissolution for bezoar located in the gastric pouch. Clinical and in vitro studies show the efficacy of both papain and cellulase, and it is suggested that, since each acts on a different component of the bezoar, they be administered in combination. There were no complications with this treatment in the patients reported in this series.