Parenteral iron therapy in obstetrics: 8 years experience with iron-sucrose complex

Fe is an essential component of haem in myoglobin and accounts for 70 % of haemoglobin. The balance of Fe, unlike that of other metals such as Na or Ca, is regulated solely by gastrointestinal absorption, which itself depends on the bioavailability of Fe in food, i.e. the chemical Fe species. Factors that maintain Fe homeostasis by modulating Fe transfer through the intestinal mucosa are found at the luminal, mucosal and systemic levels. Fe deficiency and its consequence, Fe-deficiency anaemia, form the commonest nutritional pathology in pregnant women. The current gold standard to detect Fe deficiency remains the serum ferritin value. Previously there was general consensus against parenteral Fe administration, i.e. parenteral Fe was only recommended for special conditions such as unresponsiveness to oral Fe, intolerance to oral Fe, severe anaemia, lack of time for therapy etc. However, especially in hospital settings, clinicians regularly face these conditions but are still worried about reactions that were described using Fe preparations such as Fe-dextrans. A widely used and safe alternative is the Fe-sucrose complex, which has become of major interest to prevent functional Fe deficiency after use of recombinant erythropoietin Numerous reports show the effectiveness and safety of the Fe-sucrose complex. Good tolerance to this Fe formulation is partly due to the low allergenic effect of the sucrose complex, partly due to slow release of elementary Fe from the complex. Accumulation of Fe-sucrose in parenchyma of organs is low compared with Fe-dextrans or Fe-gluconate, while incorporation into the bone marrow for erythropoiesis is considerably faster. Oral Fe is only started if haemoglobin levels are below 110 g/l. If levels fall below 100 g/l or are below 100 g/l at time of diagnosis, parenteral Fe-sucrose is used primarily. In cases of severe anaemia (haemoglobin <90 g/l) or non-response to parenteral Fe after 2 weeks, recombinant erythropoietin is considered in combination. By using parenteral Fe-sucrose in cases of severe Fe deficiency, anaemia during pregnancy is treated efficiently and safely according to our results and rate of blood transfusion could be reduced considerably to below 1 % of patients per yea

Culture and establishment of self-renewing human and mouse adult liver and pancreas 3D organoids and their genetic manipulation.

Adult somatic tissues have proven difficult to expand in vitro, largely because of the complexity of recreating appropriate environmental signals in culture. We have overcome this problem recently and developed culture conditions for adult stem cells that allow the long-term expansion of adult primary tissues from small intestine, stomach, liver and pancreas into self-assembling 3D structures that we have termed 'organoids'. We provide a detailed protocol that describes how to grow adult mouse and human liver and pancreas organoids, from cell isolation and long-term expansion to genetic manipulation in vitro. Liver and pancreas cells grow in a gel-based extracellular matrix (ECM) and a defined medium. The cells can self-organize into organoids that self-renew in vitro while retaining their tissue-of-origin commitment, genetic stability and potential to differentiate into functional cells in vitro (hepatocytes) and in vivo (hepatocytes and endocrine cells). Genetic modification of these organoids opens up avenues for the manipulation of adult stem cells in vitro, which could facilitate the study of human biology and allow gene correction for regenerative medicine purposes. The complete protocol takes 1-4 weeks to generate self-renewing 3D organoids and to perform genetic manipulation experiments. Personnel with basic scientific training can conduct this protocol.LB is supported by an EMBO Postdoctoral fellowship (EMBO ALTF 794-2014). CH is supported by a Cambridge Stem Cell Institute Seed Fund award and the Herchel Smith Fund. BK is supported by a Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society. MH is a Wellcome Trust Sir Henry Dale Fellow and is jointly funded by the Wellcome Trust and the Royal Society (104151/Z/14/Z).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nprot.2016.097

MRI of female genital tract congenital anomalies: European Society of Urogenital Radiology (ESUR) guidelines

OBJECTIVE: To develop imaging guidelines for the MR work-up of female genital tract congenital anomalies (FGTCA). METHODS: These guidelines were prepared based on a questionnaire sent to all members of the European Society of Urogenital Radiology (ESUR) Female Pelvic Imaging Working Group (FPI-WG), critical review of the literature and expert consensus decision. RESULTS: The returned questionnaires from 17 different institutions have shown reasonable homogeneity of practice. Recommendations with focus on patient preparation and MR protocol are proposed, as these are key to optimised examinations. Details on MR sequences and planning of uterus-orientated sequences are provided. CONCLUSIONS: The multiplanar capabilities and soft tissue resolution of MRI provide superb characterisation of the wide spectrum of findings in FGTCA. A standardised imaging protocol and method of reporting ensures that the salient features are recognised, contributing to a correct diagnosis and classification of FGTCA, associated anomalies and complications. These imaging guidelines are based on current practice among expert radiologists in the field and incorporate up to date information regarding MR protocols and essentials of recently published classification systems. KEY POINTS: * MRI allows comprehensive evaluation of female genital tract congenital anomalies, in a single examination. * A dedicated MRI protocol comprises uterus-orientated sequences and vaginal and renal evaluation. * Integration of classification systems and structured reporting helps in successful communication of the imaging findings

Syntheses, Structures, and Photophysical Properties of Mono- and Dinuclear Sulfur-Rich Gold(I) Complexes

Sulfur-rich 1,2 dithiolene and neutral thione ligands were used for the synthesis of gold complexes, some of them exhibiting aurophilic interactions. Surprisingly, the closest Au···Au contact is observed in an unsupported dinuclear complex, which makes part of a supramolecular network. Photophysical studies, combined with DFT calculations, indicate that the participations of the Au···Au interactions have some relevance to the rich luminescence properties of these compounds

Defining Lineage Potential and Fate Behavior of Precursors during Pancreas Development

Pancreas development involves a coordinated process in which an early phase of cell segregation is followed by a longer phase of lineage restriction, expansion, and tissue remodeling. By combining clonal tracing and whole-mount reconstruction with proliferation kinetics and single-cell transcriptional profiling, we define the functional basis of pancreas morphogenesis. We show that the large-scale organization of mouse pancreas can be traced to the activity of self-renewing precursors positioned at the termini of growing ducts, which act collectively to drive serial rounds of stochastic ductal bifurcation balanced by termination. During this phase of branching morphogenesis, multipotent precursors become progressively fate-restricted, giving rise to self-renewing acinar-committed precursors that are conveyed with growing ducts, as well as ductal progenitors that expand the trailing ducts and give rise to delaminating endocrine cells. These findings define quantitatively how the functional behavior and lineage progression of precursor pools determine the large-scale patterning of pancreatic sub-compartments

Staging of uterine cervical cancer with MRI: guidelines of the european society of urogenital radiology

Objective: To design clear guidelines for the staging and follow-up of patients with uterine cervical cancer, and to provide the radiologist with a framework for use in multidisciplinary conferences. Methods: Guidelines for uterine cervical cancer staging and follow-up were defined by the female imaging subcommittee of the ESUR (European Society of Urogenital Radiology) based on the expert consensus of imaging protocols of 11 leading institutions and a critical review of the literature. Results: The results indicated that high field Magnetic Resonance Imaging (MRI) should include at least two T2-weighted sequences in sagittal, axial oblique or coronal obliqu

RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state

RNF43/ZNRF3 negatively regulate WNT signalling. Both genes are mutated in several types of cancers, however, their contribution to liver disease is unknown. Here we describe that hepatocyte-specific loss of Rnf43/Znrf3 results in steatohepatitis and in increase in unsaturated lipids, in the absence of dietary fat supplementation. Upon injury, Rnf43/Znrf3 deletion results in defective hepatocyte regeneration and liver cancer, caused by an imbalance between differentiation/proliferation. Using hepatocyte-, hepatoblast- and ductal cell-derived organoids we demonstrate that the differentiation defects and lipid alterations are, in part, cell-autonomous. Interestingly, ZNRF3 mutant liver cancer patients present poorer prognosis, altered hepatic lipid metabolism and steatohepatitis/NASH signatures. Our results imply that RNF43/ZNRF3 predispose to liver cancer by controlling the proliferative/differentiation and lipid metabolic state of hepatocytes. Both mechanisms combined facilitate the progression towards malignancy. Our findings might aid on the management of those RNF43/ZNRF3 mutated individuals at risk of developing fatty liver and/or liver cancer

ICAM-1 nanoclusters regulate hepatic epithelial cell polarity by leukocyte adhesion-independent control of apical actomyosin

Epithelial intercellular adhesion molecule (ICAM)-1 is apically polarized, interacts with, and guides leukocytes across epithelial barriers. Polarized hepatic epithelia organize their apical membrane domain into bile canaliculi and ducts, which are not accessible to circulating immune cells but that nevertheless confine most of ICAM-1. Here, by analyzing ICAM-1_KO human hepatic cells, liver organoids from ICAM-1_KO mice and rescue-of-function experiments, we show that ICAM-1 regulates epithelial apicobasal polarity in a leukocyte adhesion-independent manner. ICAM-1 signals to an actomyosin network at the base of canalicular microvilli, thereby controlling the dynamics and size of bile canalicular-like structures. We identified the scaffolding protein EBP50/NHERF1/ SLC9A3R1, which connects membrane proteins with the underlying actin cytoskeleton, in the proximity interactome of ICAM-1. EBP50 and ICAM-1 form nano-scale domains that overlap in microvilli, from which ICAM-1 regulates EBP50 nano-organization. Indeed, EBP50 expression is required for ICAM-1-mediated control of BC morphogenesis and actomyosin. Our findings indicate that ICAM-1 regulates the dynamics of epithelial apical membrane domains beyond its role as a heterotypic cell– cell adhesion molecule and reveal potential therapeutic strategies for preserving epithelial architecture during inflammatory stress