The orderly and sequential activation of genes during development is hypothesized to be related to the selective expression of groups of regulatory proteins acting primarily at the level of transcription. A nuclear protein was found in hepatocytes, but not other cell types, that binds to a sequence required for hepatocyte-specific transcription of the gene for the beta chain of fibrinogen. This protein, hepatocyte nuclear factor 1 (HNF1), also interacts with homologous sequences required for optimal promoter function of the genes for the alpha chain of fibrinogen and alpha 1-antitrypsin. The promoter or enhancer regions for several viral and cellular genes not expressed in the liver did not compete for this binding. The restricted expression of HNF1 and its selective interaction with the control regions of several liver-specific genes indicate that it is involved in developmentally regulated gene expression in the liver.

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Between October 6, 1986 and September 17, 1987, 11 patients underwent insertion of mandibular dental prostheses by the same oral surgeon. Three patients suffered cardiac arrest during surgery and subsequently died. Two of the patients who died had received general anaesthetics and the other had intravenous sedation given by three different anaesthetists. All three patients arrested suddenly, developing profound cyanosis and electrical mechanical dissociation, underwent prolonged resuscitative efforts, and had marked hypoxaemia and hypercapnia, despite cardiopulmonary resuscitation. Two other patients had signs of injection of air but survived, one suffering cardiac collapse and the other sustaining massive subcutaneous emphysema. Air embolism was produced by inadvertent injection of a mixture of air and water, passing through the hollow dental drill, directly into the mandible to the facial and pterygoid plexus veins and thence to the superior vena cava and right atrium.

To study the factors which influence the coordinately and developmentally regulated expression of the three adjacent fibrinogen genes, we have defined the functional regions of the -y-fibrinogen promoter and the proteins which bind to them. Using a series of 5' and internal deletion mutations, we found that sequences between 88 and 43 base pairs (bp) upstream of the y-fibrinogen transcription initiation site functioned in cis to direct properly initiated mRNA accumulation in transfected hepatocytes. The efficient function of these sequences was highly distance dependent, since transcriptional activity decreased by 92% when they were moved 32 bp upstream of the TATA box. We demonstrated that two known and one putative transcriptional factors interacted with this 47-bp sequence. The transcription factor Spl interacted with sequences between -51 and -46 as demonstrated by protection from DNase I digestion with the purified protein. Directly adjacent to the Spl site, between nucleotides -66 and -53, there was a sequence which bound a CAAT-binding factor. Finally, sequences just 5' to the CAAT factor-binding site interacted with the adenovirus major late transcriptional factor as previously demonstrated. Internal deletion mutations which disrupt these interactions diminished the activity of the promoter in vivo. One consequence of the interaction of these proteins is that a bend is placed in the DNA at or near their sites of interaction.Fibrinogen is the product of three genes (a, 3, and -y) linked on a 46-kilobase (kb) region of human chromosome 4 (21). Transcription of these three genes is coordinately regulated and selectively confined to hepatocytes and megakaryocytes (6, 40). Coordinate regulation of these three genes is expected since the mature fibrinogen molecule is made up of two a, two ,B, and two y chains. Since these genes originated over 1.5 billion years ago, long before the origin of a three-chain fibrinogen molecule (11) or even a coagulation system, we assume that the mechanisms used to achieve similar levels of transcription of these three genes in present-day vertebrates are evolutionarily convergent. Thus, the molecules which control the transcription of these three genes could be quite different unless they are preserved from the ancient organism in which the fibrinogen gene first duplicated over 1.5 billion years ago (11).Information gained by the analysis of a number of viral promoters has indicated that eucaryotic transcription promoters are a mosaic of regulatory elements. These regulatory elements appear to act by binding multiple factors which influence transcriptional rates in both qualitative and quantitative manners. The present views of the function of the simian virus 40 combinational use of a defined but varied group of transcriptional factors. In this paper, we describe the functional sequences and nuclear factors involved in the transcriptional regulation of the y-fibrinogen (y-FIB) promoter. The findings indicate that two known and one putative transcriptional factors bind and ...

Background Patient blood management (PBM) describes a set of evidence-based practices to optimize medical and surgical patient outcomes by clinically managing and preserving a patient’s own blood. This concepts aims to detect and treat anemia, minimize the risk for blood loss and the need for blood replacement for each patient through a coordinated multidisciplinary care process. In combination with blood loss, anemia is the main driver for transfusion and all three are independent risk factors for adverse outcomes including morbidity and mortality. Evidence demonstrates that PBM significantly improves outcomes and safety while reducing cost by macroeconomic magnitudes. Despite its huge potential to improve healthcare systems, PBM is not yet adopted broadly. The aim of this study is to analyze the collective experiences of a diverse group of PBM implementors across countries reflecting different healthcare contexts and to use these experiences to develop a guidance for initiating and orchestrating PBM implementation for stakeholders from diverse professional backgrounds. Methods Semi-structured interviews were conducted with 1–4 PBM implementors from 12 countries in Asia, Latin America, Australia, Central and Eastern Europe, the Middle East, and Africa. Responses reflecting the drivers, barriers, measures, and stakeholders regarding the implementation of PBM were summarized per country and underwent qualitative content analysis. Clustering the resulting implementation measures by levels of intervention for PBM implementation informed a PBM implementation framework. Results A set of PBM implementation measures were extracted from the interviews with the implementors. Most of these measures relate to one of six levels of implementation including government, healthcare providers, funding, research, training/education, and patients/public. Essential cross-level measures are multi-stakeholder communication and collaboration. Conclusion The implementation matrix resulting from this research helps to decompose the complexity of PBM implementation into concrete measures on each implementation level. It provides guidance for diverse stakeholders to design, initiate and develop strategies and plans to make PBM a national standard of care, thus closing current practice gaps and matching this unmet public health need.