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Solstad T.,University of Oslo | Solstad T.,Norwegian Medicines Agency | Bains S.J.,University of Oslo | Landskron J.,University of Oslo | And 5 more authors.
Blood | Year: 2011

Human CD4 +FoxP3 + T cells are functionally and phenotypically heterogeneous providing plasticity to immune activation and regulation. To better understand the functional dynamics within this subset, we first used a combined strategy of subcellular fractionation and proteomics to describe differences at the protein level between highly purified human CD4 +CD25 + and CD4 +CD25 - T-cell populations. This identified a set of membrane proteins highly expressed on the cell surface of human regulatory T cells (Tregs), including CD71, CD95, CD147, and CD148. CD147 (Basigin or Emmprin) divided CD4 +CD25 + cells into distinct subsets. Furthermore, CD147, CD25, FoxP3, and in particular CTLA-4 expression correlated. Phenotypical and functional analyses suggested that CD147 marks the switch between resting (CD45RA +) and activated (CD45RO +) subsets within the FoxP3 + T-cell population. Sorting of regulatory T cells into CD147 -and CD147 + populations demonstrated that CD147 identifies an activated and highly suppressive CD45RO + Treg subset. When analyzing CD4 + T cells for their cytokine producing potential, CD147 levels grouped the FoxP3 + subset into 3 categories with different ability to produce IL-2, TNF-α, IFN-γ, and IL-17. Together, this suggests that CD147 is a direct marker for activated Tregs within the CD4 +FoxP3 + subset and may provide means to manipulate cells important for immune homeostasis. © 2011 by The American Society of Hematology. Source


Ruiz B.Q.,European Medicines Agency | Desfontaine E.,European Medicines Agency | Arenas-Lopez S.,Evelina Childrens Hospital | Wang S.,Norwegian Medicines Agency
Expert Review of Clinical Pharmacology | Year: 2014

Since the European Paediatric Regulation was introduced in 2007, companies developing new medicinal products or new indications/routes of administration/pharmaceutical forms are obliged to present age-appropriate formulations for the pediatric population within a Paediatric Investigation Plan (PIP) to the European Medicines Agency. Our review highlights a number of discrepancies between what is proposed by applicants and what is considered acceptable by regulators, taking a sample of PIP applications assessed by a specialized Formulation Working Group (FWG) of the Paediatric Committee in 2009. This Working Group assessed 43% of the total number of validated PIP applications during that year. Ninety-two percent of the formulations assessed raised at least one issue, mainly relating to excipients, appropriateness of the route of administration or pharmaceutical form, dosing accuracy and patient's acceptability. A stronger focus on all these aspects, considering the targeted age range, the severity of the disease and the treatment duration, could streamline the development process. © 2014 Informa UK Ltd. Source


Blystad H.,Norwegian Institute of Public Health | Anestad G.,Norwegian Institute of Public Health | Vestrheim D.F.,Norwegian Institute of Public Health | Madsen S.,Norwegian Medicines Agency | Ronning K.,Norwegian Institute of Public Health
Eurosurveillance | Year: 2012

Epidemics of Mycoplasma pneumoniae have recently been reported from England and Wales and from Denmark. A similar increase in M. pneumoniae infections was noted in Norway late autumn 2011.The epidemic has resulted in shortage of erythromycin and the use of alternative antibiotics has been recommended. Source


Pidoux G.,French Institute of Health and Medical Research | Pidoux G.,University of Paris Descartes | Pidoux G.,University of Oslo | Gerbaud P.,French Institute of Health and Medical Research | And 9 more authors.
Journal of Cell Science | Year: 2014

Cell fusion occurs as part of the differentiation of some cell types, including myotubes in muscle and osteoclasts in remodeling bone. In the human placenta, mononuclear cytotrophoblasts in a human chorionic gonadotropin (hCG)-driven process fuse to form multinucleated syncytia that allow the exchange of nutrients and gases between the maternal and fetal circulation. Experiments in which protein kinase A (PKA) is displaced from A-kinase anchoring proteins (AKAPs), or in which specific AKAPs are depleted by siRNA-mediated knockdown, point to ezrin as a scaffold required for hCG-, cAMP- and PKA-mediated regulation of the fusion process. By a variety of immunoprecipitation and immunolocalization experiments, we show that ezrin directs PKA to a molecular complex of connexin 43 (Cx43, also known as GJA1) and zona occludens-1 (ZO-1, also known as TJP1). A combination of knockdown experiments and reconstitution with ezrin or Cx43 with or without the ability to bind to its interaction partner or to PKA demonstrate that ezrin-mediated coordination of the localization of PKA and Cx43 is necessary for discrete control of Cx43 phosphorylation and hCG-stimulated gap junction communication that triggers cell fusion in cytotrophoblasts. © 2014. Published by The Company of Biologists Ltd. Source


Bramness J.G.,University of Oslo | Bramness J.G.,Norwegian Institute of Public Health | Khiabani H.Z.,Norwegian Institute of Public Health | Khiabani H.Z.,Norwegian Medicines Agency | And 2 more authors.
Addiction | Year: 2010

Aims Studies have shown that the impairing effects of Δ-9- tetrahydrocannabinol (THC) are dose-related. Cannabis intake increases the risk of traffic accidents. The purpose of this study was to see how different clinical tests and observations were related to blood THC concentrations and to determine whether the combined influence of THC and ethanol was different from either drug alone. Design A retrospective cross-sectional forensic database study. Setting Drivers apprehended by the police suspected of driving under the influence of alcohol other drugs. Participants We investigated 589 cases positive for THC only. In addition, 894 cases with THC and ethanol were included. A comparison was made with 3480 drivers with only ethanol in their blood and 79 drivers who tested negative. Measurements Data were analytical results of blood samples and the 27 clinical tests and observations included in the Norwegian clinical test for impairment (CTI). Findings No relationship was found between blood THC concentration and most of the CTI tests. Blood THC concentration was, however, related to conjunctival injection, pupil dilation and reaction to light and to the overall risk of being judged impaired. When THC and ethanol were detected together the risk of being judged impaired was increased markedly. Conclusions This study demonstrates that cannabis impairs driving ability in a concentration-related manner. The effect is smaller than for ethanol. The effect of ethanol and cannabis taken simultaneously is additive. Conjunctival injection, dilated pupils and slow pupil reaction are among the few signs to reveal THC influence. © 2010 Society for the Study of Addiction. Source

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