Clinical and pathophysiological aspects of intrahepatic cholestasis of pregnancy

Objective: The pathogenesis of intrahepatic cholestasis of pregnancy (ICP) involves impaired bile acid and estrogen/progesterone metabolism and excretion based on genetic and environmental factors. In this thesis we evaluated different pathophysiological and clinical aspects of ICP, i.e., serum levels of vitamin D, the morphology of ICP placentas, maternal and fetal outcomes in ICP at a time of active management, and ICP-associated pregnancy conditions. Methods: In Paper I, we performed an observational study and compared the levels of active vitamin D (1,25-dihydroxy vitamin D3) in women with ICP and normal pregnancies. In Paper II we examined in a prospective case-control study morphological differences of placentas from untreated and ursodeoxycholic acid (UDCA) treated ICP, respectively, and normal pregnancies, by using stereology and systematic random sampling. In paper III, we estimated in a nationwide cohort study of more than 1.2 million singleton births in Sweden between 1997 and 2009 the actual prevalence of ICP and its association with adverse pregnancy and fetal outcomes, using data of the Swedish Medical Birth Registry (MBR). In Paper IV, we assessed in a hospital based retrospective cohort study the risk of emergency cesarean section (CS) and fetal asphyxia in ICP women with spontaneous and induced onset of labor at gestational weeks 37-39, by linkage of the MBR and a local obstetrical database. Results: We report for the first time that women with ICP have lower levels of active vitamin D. We also show that ICP substantially affects the morphology of the placenta, with increased surface capillary area and syncytial knots. These changes were not observed in UDCA-treated ICP. In our nationwide population based study, we found a previously unknown strong association of ICP with gestational diabetes, preeclampsia and large for gestational age, and that ICP bears an increased risk of moderate prematurity but not of stillbirth at a time of active management. We found that induction of labor in women with ICP in gestational weeks 37-39 in a tertiary Swedish hospital did not increase the risks of emergency CS or fetal asphyxia. Conclusions: Decreased levels of active vitamin D may contribute to the pathogenesis of ICP. ICP causes morphological changes in the placenta that might be improved by treatment with UDCA. Induction of labor in ICP does not increase the rate of emergency CS. The low risk of stillbirths at a time of modern management of ICP is reassuring but the strong association of ICP with gestational diabetes and preeclampsia needs consideration, e.g., by oral glucose tolerance testing and proper management of possibly coexisting conditions

A global disorder of imprinting in the human female germ line

Imprinted genes are expressed differently depending on whether they are carried by a chromosome of maternal or paternal origin. Correct imprinting is established by germline-specific modifications; failure of this process underlies several inherited human syndromes. All these imprinting control defects are cis-acting, disrupting establishment or maintenance of allele-specific epigenetic modifications across one contiguous segment of the genome. In contrast, we report here an inherited global imprinting defect. This recessive maternal-effect mutation disrupts the specification of imprints at multiple, non-contiguous loci, with the result that genes normally carrying a maternal methylation imprint assume a paternal epigenetic pattern on the maternal allele. The resulting conception is phenotypically indistinguishable from an androgenetic complete hydatidiform mole, in which abnormal extra-embryonic tissue proliferates while development of the embryo is absent or nearly so. This disorder offers a genetic route to the identification of trans-acting oocyte factors that mediate maternal imprint establishment

Electromigration-Induced Propagation of Nonlinear Surface Waves

Due to the effects of surface electromigration, waves can propagate over the free surface of a current-carrying metallic or semiconducting film of thickness h_0. In this paper, waves of finite amplitude, and slow modulations of these waves, are studied. Periodic wave trains of finite amplitude are found, as well as their dispersion relation. If the film material is isotropic, a wave train with wavelength lambda is unstable if lambda/h_0 < 3.9027..., and is otherwise marginally stable. The equation of motion for slow modulations of a finite amplitude, periodic wave train is shown to be the nonlinear Schrodinger equation. As a result, envelope solitons can travel over the film's surface.Comment: 13 pages, 2 figures. To appear in Phys. Rev.

Beta cell death by cell-free DNA and outcome after clinical islet transplantation

Background: Optimizing engraftment and early survival after clinical islet transplantation is critical to long-term function, but there are no reliable, quantifiable measures to assess beta cell death. Circulating cell free DNA (cfDNA) derived from beta cells has been identified as a novel biomarker to detect cell loss, and was recently validated in new-onset type 1 diabetes and in islet transplant patients. Methods: Herein we report beta cell cfDNA measurements after allotransplantation in 37 subjects and the correlation with clinical outcomes. Results: A distinctive peak of cfDNA was observed 1hr after transplantation in 31/37 (83.8%) of subjects. The presence and magnitude of this signal did not correlate with transplant outcome. The 1hr signal represents dead beta cells carried over into the recipient after islet isolation and culture, combined with acute cell death post infusion. Beta cell cfDNA was also detected 24hrs post-transplant (8/37 subjects, 21.6%). This signal was associated with higher 1-month insulin requirements (p=0.04), lower 1-month stimulated C-peptide levels (p=0.01) and overall worse 3-month engraftment, by insulin independence (ROC:AUC=0.70, p=0.03) and Beta 2 score (ROC:AUC=0.77, p=0.006). Conclusions: cfDNA-based estimation of beta cell death 24hrs after islet allotransplantation correlates with clinical outcome and could predict early engraftment.B.G.-L. is supported through the Alberta Innovates :Health Solutions (AIHS) Clinician Fellowship and through the CNTRP. A.P. is supported through AIHS Postgraduate Fellowship and CNTRP. A.M.J.S. is supported through AIHS, and holds a Canada Research Chair in Transplantation Surgery and Regenerative Medicine funded through the Government of Canada. A.M.J.S. is also funded by AIHS Collaborative Research and Innovation Opportunity Team Award and the Diabetes Research Institute Foundation of Canada (DRIFCan). Supported by grants from the Juvenile Diabetes Research Foundation (JDRF) (3-SRA-2014-38-Q-R, to Y.D. and A.M.J.S.), National Institute of Health (NIH) (HIRN grant UC4 DK104216, to Y.D.), DON foundation (Stichting Diabetes Onderzoek Nederland) (to Y.D), the European Union (ELASTISLET project, to Y.D.) and the Kahn foundation (to Y.D., R.S., and B.G.). Supported in part by a grant from The United States Agency for International Development (USAID) American Schools and Hospitals Abroad Program for the upgrading of the Hebrew University sequencing core facilit

Processes, contexts, and rationale for disinvestment: a protocol for a critical interpretive synthesis

Background: Practical solutions are needed to support the appropriate use of available health system resources as countries are continually pressured to ‘do more with less’ in health care. Increasingly, health systems and organizations are exploring the reassessment of possibly obsolete, inefficient, or ineffective health system resources and potentially redirecting funds to those that are more effective and efficient. Such processes are often referred to as ‘disinvestment’. Our objective is to gain further understanding about: 1) whether how and under what conditions health systems decide to pursue disinvestment; 2) how health systems have chosen to undertake disinvestment; and 3) how health systems have implemented their disinvestment approach. Methods/Design We will use a critical interpretive synthesis (CIS) approach, to develop a theoretical framework based on insights drawn from a range of relevant sources. We will conduct systematic searches of databases as well as purposive searches to identify literature to fill conceptual gaps that may emerge during our inductive process of synthesis and analysis. Two independent reviewers will assess search results for relevance and conceptually map included references. We will include all empirical and non-empirical articles that focus on disinvestment at a system level. We will then extract key findings from a purposive sample of articles using frameworks related to government agendas, policy development and implementation, and health system contextual factors and then synthesize and integrate the findings to develop a framework about our core areas of interest. Lastly, we will convene a stakeholder dialogue with Canadian and international policymakers and other stakeholders to solicit targeted feedback about the framework (e.g., by identifying any gaps in the literature that we may want to revisit before finalizing it) and deliberating about barriers for developing and implementing approaches to disinvestment, strategies to address these barriers and about next steps that could be taken by different constituencies. Discussion Disinvestment is an emerging field and there is a need for evidence to inform the prioritization, development, and implementation of strategies in different contexts. Our CIS and the framework developed through it will support the actions of those involved in the prioritization, development, and implementation of disinvestment initiatives. Systematic review registration PROSPERO CRD42014013204 Electronic supplementary material The online version of this article (doi:10.1186/2046-4053-3-143) contains supplementary material, which is available to authorized users

Diffractive Guiding of Waves by a Periodic Array of Slits

We show that in order to guide waves, it is sufficient to periodically truncate their edges. The modes supported by this type of wave guide propagate freely between the slits, and the propagation pattern repeats itself. We experimentally demonstrate this general wave phenomenon for two types of waves: (i) plasmonic waves propagating on a metal-air interface that are periodically blocked by nanometric metallic walls, and (ii) surface gravity water waves whose evolution is recorded, the packet is truncated, and generated again to show repeated patterns. This guiding concept is applicable for a wide variety of waves.Comment: 5 pages, 4 figure

The EFF-1A Cytoplasmic Domain Influences Hypodermal Cell Fusions in C. elegans But Is Not Dependent on 14-3-3 Proteins.

BACKGROUND: Regulatory and biophysical mechanisms of cell-cell fusion are largely unknown despite the fundamental requirement for fused cells in eukaryotic development. Only two cellular fusogens that are not of clear recent viral origin have been identified to date, both in nematodes. One of these, EFF-1, is necessary for most cell fusions in Caenorhabditis elegans. Unregulated EFF-1 expression causes lethality due to ectopic fusion between cells not developmentally programmed to fuse, highlighting the necessity of tight fusogen regulation for proper development. Identifying factors that regulate EFF-1 and its paralog AFF-1 could lead to discovery of molecular mechanisms that control cell fusion upstream of the action of a membrane fusogen. Bioinformatic analysis of the EFF-1A isoform\u27s predicted cytoplasmic domain (endodomain) previously revealed two motifs that have high probabilities of interacting with 14-3-3 proteins when phosphorylated. Mutation of predicted phosphorylation sites within these motifs caused measurable loss of eff-1 gene function in cell fusion in vivo. Moreover, a human 14-3-3 isoform bound to EFF-1::GFP in vitro. We hypothesized that the two 14-3-3 proteins in C. elegans, PAR-5 and FTT-2, may regulate either localization or fusion-inducing activity of EFF-1. METHODOLOGY/PRINCIPAL FINDINGS: Timing of fusion events was slightly but significantly delayed in animals unable to produce full-length EFF-1A. Yet, mutagenesis and live imaging showed that phosphoserines in putative 14-3-3 binding sites are not essential for EFF-1::GFP accumulation at the membrane contact between fusion partner cells. Moreover, although the EFF-1A endodomain was required for normal rates of eff-1-dependent epidermal cell fusions, reduced levels of FTT-2 and PAR-5 did not visibly affect the function of wild-type EFF-1 in the hypodermis. CONCLUSIONS/SIGNIFICANCE: Deletion of the EFF-1A endodomain noticeably affects the timing of hypodermal cell fusions in vivo. However, prohibiting phosphorylation of candidate 14-3-3-binding sites does not impact localization of the fusogen. Hypodermal membrane fusion activity persists when 14-3-3 expression levels are reduced

Totally Splittable Polytopes

A split of a polytope is a (necessarily regular) subdivision with exactly two maximal cells. A polytope is totally splittable if each triangulation (without additional vertices) is a common refinement of splits. This paper establishes a complete classification of the totally splittable polytopes.Comment: 15 pages, 7 figures; v2: major revision: corrections of some minor errors and some addition

Hepatitis C virus infection among transmission-prone medical personnel

Hepatitis C virus (HCV)-infected physicians have been reported to infect some of their patients during exposure-prone procedures (EPPs). There is no European consensus on the policy for the prevention of this transmission. To help define an appropriate preventive policy, we determined the prevalence of HCV infection among EPP-performing medical personnel in the Academic Medical Center in Amsterdam, the Netherlands. The prevalence of HCV infection was studied among 729 EPP-performing health care workers. Serum samples, stored after post-hepatitis B virus (HBV) vaccination testing in the years 2000–2009, were tested for HCV antibodies. Repeat reactive samples were confirmed by immunoblot assay and the detection of HCV RNA. The average age of the 729 health care workers was 39 years (range 18–66), suggesting a considerable cumulative occupational exposure to the blood. Nevertheless, only one of the 729 workers (0.14%; 95% confidence interval [CI]: <0.01% to 0.85%) was tested and confirmed to be positive for anti-HCV and positive for HCV RNA, which is comparable to the prevalence of HCV among Amsterdam citizens. Against this background, for the protection of personnel and patients, careful follow-up after needlestick injuries may be sufficient. If a zero-risk approach is desirable and costs are less relevant, the recurrent screening of EPP-performing personnel for HCV is superior to the follow-up of reported occupational exposures