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Bannwarth B.,University of Bordeaux Segalen
Drugs | Year: 2012

During the last 2 decades, there has been a dramatic increase in the use of strong opioids for chronic non-cancer pain. This increase has been accompanied by a steep increase in abuse, misuse, and both fatal and non-fatal overdoses involving prescription opioids. The situation is already alarming in the US. Prescription opioid-related harm is a complex, multifactorial issue that requires a multifaceted solution. In this respect, formulations of opioid analgesics designed to resist or deter abuse may be a useful component of a comprehensive opioid risk minimization programme. Such formulations have or are being developed. Abuse-resistant opioids include those that use some kind of physical barrier to prevent tampering with the formulation. Abuse-deterrent opioids are not necessarily resistant to tampering, but contain substances that are designed to make the formulation less attractive to abusers. This article focuses on two products intended to deter abuse that were reviewed by the US Food and Drug Administration (FDA).The first (Embeda®) consists of extended-release morphine with sequestered naltrexone, an opioid antagonist that is released if the tablet is compromised by chewing or crushing. Although Embeda® exhibited abuse-deterrent features, its label warns that it can be abused in a manner similar to other opioid agonists. Furthermore, tampering with Embeda® will result in the release of naltrexone, which may precipitate withdrawal in opioid-tolerant individuals. In March 2011, all dosage forms of Embeda® were recalled because the product failed to meet routine stability standards, and its return date to the market is currently unknown. The second product (Acurox®) was intended to be both tamper resistant and abuse deterrent. It consisted of an immediate-release oxycodone tablet with subtherapeutic niacin as an aversive agent and used a gel-forming ingredient designed to inhibit inhalation and prevent extraction of the drug for injection. The new drug application for Acurox® was rejected in 2010 by the FDA because of concerns about the potential abuse-deterrent benefits of niacin.While acknowledging that no one formulation can be expected to deter all types of opioid-abusive behaviours and no product is likely to be abuse proof in the hands of clear and determined abusers, the reductions in abuse these new products would provide may be an incremental step towards safer prescription opioids. © 2012 Springer International Publishing AG. All rights reserved. Source

Saupe S.J.,University of Bordeaux Segalen
Seminars in Cell and Developmental Biology | Year: 2011

[Het-s] is a prion from the filamentous fungus Podospora anserina and corresponds to a self-perpetuating amyloid aggregate of the HET-s protein. This prion protein is involved in a fungal self/non-self discrimination process termed heterokaryon incompatibility corresponding to a cell death reaction occurring upon fusion of genetically unlike strains. Two antagonistic allelic variants of this protein exist: HET-s, the prion form of which corresponds to [Het-s] and HET-S, incapable of prion formation. Fusion of a [Het-s] and HET-S strain triggers the incompatibility reaction, so that interaction of HET-S with the [Het-s] prion leads to cell death. HET-s and HET-S are highly homologous two domain proteins with a N-terminal globular domain termed HeLo and a C-terminal unstructured prion forming domain (PFD). The structure of the prion form of the HET-s PFD has been solved by solid state NMR and corresponds to a very well ordered β-solenoid fold with a triangular hydrophobic core. The ability to form this β-solenoid fold is retained in a distant homolog of HET-s from another fungal species. A model for the mechanism of [Het-s]/HET-S incompatibility has been proposed. It is believe that when interacting with the [Het-s] prion seed, the HET-S C-terminal region adopts the β-solenoid fold. This would act as a conformational switch to induce refolding and activation of the HeLo domain which then would exert its toxicity by a yet unknown mechanism. © 2011 Elsevier Ltd. Source

Le Huec J.C.,University of Bordeaux Segalen
European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society | Year: 2011

Bipedalism is a distinguishing feature of the human race and is characterised by a narrow base of support and an ergonomically optimal position thanks to the appearance of lumbar and cervical curves. The pelvis, adapted to bipedalism, may be considered as the pelvic vertebra connecting the spine to the lower limbs. Laterally, the body's line of gravity is situated very slightly behind the femoral heads laterally, and frontally it runs through the middle of the sacrum at a point equidistant from the two femoral heads. Any abnormal change through kyphosis regarding the spinal curves results in compensation, first in the pelvis through rotation and then in the lower limbs via knee flexion. This mechanism maintains the line of gravity within the base of support but is not ergonomic. To analyse sagittal balance, we must thus define the parameters concerned and the relationships between them. These parameters are as follows: for the pelvis: incidence angle, pelvis tilt, sacral slope; for the spine: point of inflexion, apex of lumbar lordosis, lumbar lordosis, spinal tilt at C7; for overall analysis: spino-sacral angle, which is an intrinsic parameter. Source

Harizi H.,University of Bordeaux Segalen
Cellular and Molecular Immunology | Year: 2013

The reciprocal activating crosstalk between dendritic cells (DCs) and natural killer (NK) cells plays a pivotal role in regulating immune defense against viruses and tumors. The cytokine-producing capacity, Th-cell polarizing ability and chemokine expression, migration and stimulatory functions of DCs are regulated by activated NK cells. Conversely, the innate and effector functions of NK cells require close interactions with activated DCs. Cell membrane-associated molecules and soluble mediators, including cytokines and prostaglandins (PGs), contribute to the bidirectional crosstalk between DCs and NK cells. One of the most well-known and well-studied PGs is PGE2. Produced by many cell types, PGE2 has been shown to affect various aspects of the immune and inflammatory responses by acting on all components of the immune system. There is emerging evidence that PGE2 plays crucial roles in DC and NK cell biology. Several studies have shown that DCs are not only a source of PGE2, but also a target of its immunomodulatory action in normal immune response and during immune disorders. Although NK cells appear to be unable to produce PGE2, they are described as powerful PGE2-responding cells, as they express all PGE2 E-prostanoid (EP) receptors. Several NK cell functions (lysis, migration, proliferation, cytokine production) are influenced by PGE2. This review highlights the effects of PGE2 on DC-NK cell crosstalk and its subsequent impact on immune regulations in normal and immunopathological processes. © 2013 CSI and USTC. Source

Le Huec J.C.,University of Bordeaux Segalen
European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society | Year: 2011

Treatment of spine imbalance by posterior osteotomy is a valuable technique. Several surgical techniques have been developed and proposed to redress the vertebral column in harmonious kyphosis in order to recreate correct sagittal alignment. Although surgical techniques proved to be adequate, preoperative planning still is mediocre. Multiple suggestions have been proposed, from cutting tracing paper to ingenious mathematical formulas and computerised models. The analysis of the pelvic parameters to try to recover the initial shape of the spine before the spine imbalance occurred is very important to avoid mistakes during the osteotomy planification. The authors proposed their method for the osteotomy planning paying attention to the pelvic, and spine parameters and in accordance with Roussouly's classification. The pre operative planning is based on a full-body X-ray including the spine from C1 to the femoral head and the first 10 cm of the femur shaft. Using all the balance parameters provided, a formula name FBI is proposed. Calculation of the osteotomy is basic goniometry, the midpoint of the C7 inferior plateau (point a) is transposed horizontally on the projected future C7 plumb line (point b) crossing posterior S1 plateau on a sagittal X-ray. These are the first two reference points. A third reference point is made on the anterior wall of the selected vertebra for osteotomy at mid height of the pedicle (point c) mainly L4 vertebra. These three points form a triangle with the tip being the third reference point. The angle represented by this triangle is the theoretical angle of the osteotomy. Two more angles should be measured and eventually added. The femur angulation measured as the inclination of the femoral axis to the vertical. And a third angle named the compensatory pelvic tilt to integrate the type of pelvis. If the pelvic tilt is between 15 and 25° or is higher than 25° you must add 5 or 10°, respectively. This compensatory tilt is based on a clinical analysis of operated patients. This planification was applied in a retrospective study of 18 patients and showed why in some cases improper correction was performed and prospectively in 8 cases with good clinical outcomes and correct spinal alignment. Sometimes it is necessary to find an acceptable compromise when rebalancing the spine paying attention to the general parameters of the patients like: age, osteoporosis, systemic disease etc. This FBI technique can be used even for small lordosis restoration: it gave a good evaluation of the amount of correction needed and then the surgeon had the choice to use the appropriate technique to obtain a good balance. Source

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