Esx1 dosage impacts reproductive fitness: Effects on viability and fertility

Numerous genes expressed in placenta or testis localize to the X-chromosome. Both tissues undergo specialized X-chromosome inactivation (imprinted paternal inactivation in placenta and MSCI in testicular germ cells). When the X-chromosome is duplicated or improperly inactivated, defects in placentation, growth and spermatogenesis are noted, suggesting tight control of X-chromosome gene dosage is important for reproduction. ^ Esx1 is a mouse homeobox gene on the X-chromosome with expression limited to extraembryonic tissues and testicular germ cells. Here, we examine the effects of increased and decreased Esx1 dosage on placental and testicular development, the role of genetic background on Esx1 function and characterize the human orthologue of Esx1. ^ Previously, by targeted deletion, Esx1 was shown to be an X-chromosome imprinted regulator of placental development and fetal growth. We show C57Bl6-congenic Esx1 mutants display a more severe phenotype with decreased viability and that the 129 genetic background contains dominant modifier genes that enhance Esx1 mutant survival. ^ Varying Esx1 dosage impacts testicular germ cell development. Esx1 hemizygous null mice are fertile, but we show their testes are two-thirds normal size. To examine the effect of increased Esx1 dosage, Esx1 BAC transgenic mice were generated. Increased Esx1 dosage results in dramatic deficits in testicular germ cell development, leading to sterility and testes one-fourth normal size. We show germ cell loss occurs through apoptosis, begins between postnatal day 6 and 10, and that no spermatocytes complete meiosis. Interestingly, increased Esx1 dosage in testes mimics germ cell loss seen in Klinefelter's (XXY) mice and humans and may represent a molecular mechanism for the infertility characteristic of this syndrome. ^ Esx1 dosage impacts reproductive fitness when maternally transmitted. Three transgenic founder females were unable to transmit the transgene to live offspring, but did produce transgenic pups at earlier stages. Additionally, one line of Esx1 BAC transgenic mice demonstrated decreased embryo size and fitness when the transgene is inherited compared to wild type littermates. ^ It is possible that Esx1 plays a role in human disorders of pregnancy, growth and spermatogenesis. Therefore, we cloned and characterized ESX1L (human Esx1), and show it is expressed in human testis and placenta. ^

Hospital district viability and Medicaid /market changes

Hospital districts (HD) that serve the uninsured and the needy face new challenges with the implementation of Medicaid managed. The potential loss of Medicaid patients and revenues may affect the ability to cost-shift and subsequently decrease the ability of the HD to meet its legal obligation of providing care for the uninsured. ^ To investigate HD viability in the current market, the aims of this study were to: (1) describe HD's environment, (2) document the HDs strategic response, (3) document changes in the HD's performance (patient volume) and financial status, and (4) determine whether relationships or trends exist between HD strategy, performance and financial status. ^ To achieve these aims, three Texas HDs (Fort Worth, Lubbock, and San Antonio) were selected to be evaluated. For each HD four types of strategic responses were documented and evaluated for change. In addition, the ability of each HD to sustain operations was evaluated by documenting performance and financial status changes (patient volume and financial ratios). A pre-post case study design method was used in which the Medicaid managed care “rollout'” date, at each site, was the central date. First, a descriptive analysis was performed which documented the environment, strategy, financial status, and patient volume of each hospital district. Second, to compare hospital districts, each hospital district was: (i) classified by a risk index, (ii) classified by its strategic response profile, and (iii) given a performance score based upon pre-post changes in patient volume and financial indicators. ^ Results indicated that all three HDs operate in a high risk environment compared to the rest of the nation. Two HDs chose the “Status Quo” response whereas one HD chose the “Competitive Proactive” response. Medicaid patient volume decreased in two of three HDs whereas indigent patient volume increased in two of the three (an indication of increasing financial risk). Total patient revenues for all HDs increased over the study period; however, the rate of increase slowed for all three after the Medicaid rollout date. All HDs experienced a decline in financial status between pre-post periods with the greatest decline observed in the HD that saw the greatest increase in indigent patient volume. ^ The pre-post case study format used and the lack of control study sites do not allow for assignment of causality. However, the results suggest possible adverse effects of Medicaid managed care and the need for a larger study, based on a stronger evaluation research design. ^