Exposure considerations in human safety assessment: Report from an EPAA Partners' Forum.

Understanding and estimating the exposure to a substance is one of the fundamental requirements for safe manufacture and use. Many approaches are taken to determine exposure to substances, mainly driven by potential use and regulatory need. There are many opportunities to improve and optimise the use of exposure information for chemical safety.

Acceptance of oclacitinib maleate (Apoquel®) chewable tablets in client-owned dogs with allergic and atopic dermatitis.

Background: The oral acceptance of oclacitinib maleate (Apoquel®) chewable tablets administered twice daily for 7 days at the labeled dose range of 0.4-0.6 mg/kg was evaluated in 121 dogs treated at ten general practice veterinary clinics in the United States.

Trauma-Induced Coagulopathy: Overview of an Emerging Medical Problem from Pathophysiology to Outcomes.

Coagulopathy induced by major trauma is common, affecting approximately one-third of patients after trauma. It develops independently of iatrogenic, hypothermic, and dilutive causes (such as iatrogenic cause in case of fluid administration), which instead have a pejorative aspect on coagulopathy. Notwithstanding the continuous research conducted over the past decade on Trauma-Induced Coagulopathy (TIC), it remains a life-threatening condition with a significant impact on trauma mortality.

Lung Ultrasound in Patients with Acute Respiratory Failure Reduces Conventional Imaging and Health Care Provider Exposure to COVID-19.

Lung ultrasound gained a leading position in the last year as an imaging technique for the assessment and management of patients with acute respiratory failure. In coronavirus disease 2019 (COVID-19), its role may be of further importance because it is performed bedside and may limit chest X-ray and the need for transport to radiology for computed tomography (CT) scan. Since February 21, we progressively turned into a coronavirus-dedicated intensive care unit and applied an ultrasound-based approach to avoid traditional imaging and limit contamination as much as possible.

An experimental model of veno-venous arterial extracorporeal membrane oxygenation.

Introduction: Veno-venous arterial extracorporeal membrane oxygenation is a hybrid-modality of extracorporeal membrane oxygenation combining veno-venous and veno-arterial extracorporeal membrane oxygenation. It may be applied to patients with both respiratory and cardio-circulatory failure.

Aim: To describe a computational spreadsheet regarding an ex vivo experimental model of veno-venous arterial extracorporeal membrane oxygenation to determine the return of cannula pairs in a single pump-driven circuit.

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine: Brussels, Belgium. 15-18 March 2016.

[This corrects the article DOI: 10.1186/s13054-016-1208-6.].

Pharmacogenomic information in drug labels: European Medicines Agency perspective.

Pharmacogenomics (PGx) has a growing impact on healthcare and constitutes one of the major pillars of personalised medicine. For the purpose of improved individualised drug treatment, there is an increasing effort to develop drugs suitable for specific subpopulations and to incorporate pharmacogenomic drug labels in existing and novel medicines. Here, we review the pharmacogenomic drug labels of all 517 medicinal products centrally approved in the European Union (EU) since the establishment of the European Medicines Agency in 1995.

Critical review on the Environmental Risk Assessment of medicinal products for human use in the centralised procedure.

In this article we analyse the Environmental Risk Assessment (ERA) of 59 medicinal products for human use authorised in the EU through the centralised procedure between 2011 and 2012, to establish whether company submissions are compliant with the European Medicines Agency (EMA) guideline and complete in terms of data and study reports provided. The most frequent questions raised by EU regulatory authorities are described, together with an evaluation of the presence and quality of ERA-related information in published regulatory assessment documents. The results of this review show recent improvement in ERA-related data presented in regulatory assessment documents available to the public while also highlighting a need to develop further guidance on environmental issues in order to assist applicants improve their ERA dossiers and overcome current shortcomings.

European Medicines Agency initiatives and perspectives on pharmacogenomics.

Pharmacogenomics, the study of variations of DNA and RNA characteristics as related to drug response, has become an integral part of drug development and pharmacovigilance, as reflected by the incorporation of pharmacogenomic data in EU product information. In this short review article, we describe recent European Medicines Agency initiatives intended to support further the implementation of pharmacogenomics in drug development and surveillance so that patients and the public can benefit from advances in genomic science and technology.

Differentiation and expansion of endothelial cells from human bone marrow CD133(+) cells.

We report a method of purifying, characterizing and expanding endothelial cells (ECs) derived from CD133(+) bone marrow cells, a subset of CD34(+) haematopoietic progenitors. Isolated using immunomagnetic sorting (mean purity 90 +/- 5%), the CD133(+) bone marrow cells were grown on fibronectin-coated flasks in M199 medium supplemented with fetal bovine serum (FBS), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and insulin growth factor (IGF-1). The CD133(+) fraction contained 95 +/- 4% CD34(+) cells, 3 +/- 2% cells expressing VEGF receptor (VEGFR-2/KDR), but did not express von Willebrand factor (VWF), VE-cadherin, P1H12 or TE-7.

Ultrastructural features of CD34+ hematopoietic progenitor cells from bone marrow, peripheral blood and umbilical cord blood.

Hematopoietic progenitor cells from different sources have been widely characterized, but their ultrastructural morphology has never been described in detail. In this study, imunomagnetically separated CD34+ cells from normal bone marrow (BM), mobilized peripheral blood (PBSC) and human umbilical cord blood (CB) were studied by transmission electron microscopy (TEM) using a cytochemical method which reveals endogenous myelo-peroxidase (MPO) activity. This technique is particularly suited for detecting early signs of the myeloid commitment.

The apoptogenic response of human myeloid leukaemia cell lines and of normal and malignant haematopoietic progenitor cells to the proteasome inhibitor PSI.

Degradation of several intracellular proteins involved in cell cycle control and tumour growth is regulated by the ubiquitin-dependent multicatalytic protease complex (proteasome). We report that proteasome inhibitor Z-Ile-Glu(OtBu)-Ala-Leucinal (PSI) was cytotoxic on most human myeloid leukaemia cell lines at IC50 doses ranging from 5 to 25 nmol/l. Additionally, PSI pre-treatment enhanced cytotoxicity by taxol and cisplatinum.

Expansion of dendritic cells derived from human CD34+ cells in static and continuous perfusion cultures.

We examined the effects of different cytokine combinations and culture conditions on the expansion and modulation of cell surface antigens of CD34+ derived dendritic cells (DCs), the most efficient antigen-presenting cells capable of stimulating resting T cells in the primary immune response. Cells with a dendritic morphology and expressing HLA-DR, CD1a, S100 and CD83 were maximally expanded under serum-free conditions with the addition of SCF, GM-CSF, TNF-alpha, TGF-beta and Flt-3 ligand (fold increase of CD1a+ cells = 102 +/- 32 after 2 weeks of culture). CD34+ cells were also grown under continuous flow conditions in an artificial capillary system: after 14d of culture, the expansion in the total cell number was lower than that of the static cultures (3.

Response of myelodysplastic syndrome bone marrow cells to multiple cytokine stimulation in liquid cultures: an in situ hybridization study.

Background And Objective: Myelodysplastic syndrome progenitor cells can be grown and expanded in long term bone marrow liquid cultures in the presence of multiple cytokines. In this study we investigated the pattern of differentiation and response to growth factors in six cases of myelodysplastic syndrome (MDS) with well-defined cytogenetic abnormalities by means of conventional cytogenetics and fluorescence in situ hybridization (FISH).

Methods: Bone marrow cells were grown in stroma-free liquid cultures in the presence of SCF, IL-3, IL-6 and GM-CSF.

Megakaryocytic progenitors can be generated ex vivo and safely administered to autologous peripheral blood progenitor cell transplant recipients.

We evaluated different culture conditions to obtain a lineage-selected proliferation of clonogenic megakaryocytic progenitors (MP). In low-density (LD) or CD34+ cell cultures, the best results were obtained in serum-free medium in the presence of megakaryocyte growth and development factor, stem cell factor, interleukin-3 (IL-3), IL-6, IL-11, FLT-ligand, and macrophage inflammatory protein-1alpha. In paired studies, expansion of LD cells was less effective than expansion of CD34+ cells, and pre-enrichment of CD34+ cells using negative depletion of lineage-positive cells produced significantly larger quantities of MP than pre-enrichment using positive selection.

Functional and morphological characterization of immunomagnetically selected CD34+ hematopoietic progenitor cells.

We evaluated the potential of immunomagnetically selected (miniMACS) progenitor cells to give rise to colony-forming cells and their precursors, detected as long-term culture-initiating cells (LTC-IC), as well as their capacity to expand in liquid cultures. A 90% mean purity, a 43.2% yield and a 55.

Cell surface changes of hemopoietic cells during normal and leukemic differentiation: an immuno-scanning electron microscopy study.

Hemopoietic cells display a wide range of cell surface antigens which are either lineage specific or acquired during differentiation. Monoclonal antibodies can be used, in conjunction with colloidal gold markers, to identify under the scanning electron microscopy (SEM) at the single cell level, specific lineage or maturation stages in the hemopoietic bone marrow. Normal bone marrow cells, either gradient separated or purified by immuno-magnetic methods and leukemic cell samples, which can be considered as "frozen" stages of hemopoietic differentiation, have been studied with this method.

Immuno-electron microscopy characterization of human bone marrow stromal cells with anti-NGFR antibodies.

Human bone marrow stromal cells have been examined with an immuno-electron microscopy technique in order to better define their structure and function in normal hematopoiesis. Bone marrow fragments from normal donors, after mild permeabilization and glutaraldehyde prefixation were labeled with the Me20.4 Mab, which recognizes the low affinity nerve growth factor (NGFR) and was recently described as specifically identifying fibroblastic-like bone marrow stromal cells.

Scanning and transmission electron microscopy of clonal peripheral blood lymphocytes in low grade non-Hodgkin's B-cell lymphomas with predominant splenomegaly.

Peripheral blood mononuclear cells (PBLs) from 14 patients with low grade non-Hodgkin's B-cell lymphomas with predominant splenomegaly were studied by means of scanning (SEM) and transmission electron microscopy (TEM). All patients had peripheral blood and bone marrow involvement, the absence of lymphoadenopathy, and, except in one case, immunophenotypic features of a malignant proliferation of mature spleen B-cells arising from outside the germinal center, but not consistent with CLL or HCL. Several distinctive cytological features were observed in PBLs of the different subgroups.