Activity of highly dispersed Co/SBA-15 catalysts (low content) in carbon black oxidation

Peer reviewedPublisher PD

A multi-omics investigation of tacrolimus off-target effects on a proximal tubule cell-line

Introduction: Tacrolimus, an immunosuppressive drug prescribed to a majority of organ transplant recipients is nephrotoxic, through still unclear mechanisms. This study on a lineage of proximal tubular cells using a multi-omics approach aims to detect off-target pathways modulated by tacrolimus that can explain its nephrotoxicity. Methods: LLC-PK1 cells were exposed to 5 µM of tacrolimus for 24 h in order to saturate its therapeutic target FKBP12 and other high-affine FKBPs and favour its binding to less affine targets. Intracellular proteins and metabolites, and extracellular metabolites were extracted and analysed by LC-MS/MS. The transcriptional expression of the dysregulated proteins PCK-1, as well as of the other gluconeogenesis-limiting enzymes FBP1 and FBP2, was measured using RT-qPCR. Cell viability with this concentration of tacrolimus was further checked until 72 h. Results: In our cell model of acute exposure to a high concentration of tacrolimus, different metabolic pathways were impacted including those of arginine (e.g., citrulline, ornithine) (p < 0.0001), amino acids (e.g., valine, isoleucine, aspartic acid) (p < 0.0001) and pyrimidine (p < 0.01). In addition, it induced oxidative stress (p < 0.01) as shown by a decrease in total cell glutathione quantity. It impacted cell energy through an increase in Krebs cycle intermediates (e.g., citrate, aconitate, fumarate) (p < 0.01) and down-regulation of PCK-1 (p < 0.05) and FPB1 (p < 0.01), which are key enzymes in gluconeogenesis and acid-base balance control. Discussion: The variations found using a multi-omics pharmacological approach clearly point towards a dysregulation of energy production and decreased gluconeogenesis, a hallmark of chronic kidney disease which may also be an important toxicity pathway of tacrolimus

Influenza Surveillance among Outpatients and Inpatients in Morocco, 1996–2009

There is limited information about the epidemiology of influenza in Africa. We describe the epidemiology and seasonality of influenza in Morocco from 1996 to 2009 with particular emphasis on the 2007-2008 and 2008-2009 influenza seasons. Successes and challenges of the enhanced surveillance system introduced in 2007 are also discussed.Virologic sentinel surveillance for influenza virus was initiated in Morocco in 1996 using a network of private practitioners that collected oro-pharyngeal and naso-pharyngeal swabs from outpatients presenting with influenza-like-illness (ILI). The surveillance network expanded over the years to include inpatients presenting with severe acute respiratory illness (SARI) at hospitals and syndromic surveillance for ILI and acute respiratory infection (ARI). Respiratory samples and structured questionnaires were collected from eligible patients, and samples were tested by immunofluorescence assays and by viral isolation for influenza viruses.We obtained a total of 6465 respiratory specimens during 1996 to 2009, of which, 3102 were collected during 2007-2009. Of those, 2249 (72%) were from patients with ILI, and 853 (27%) were from patients with SARI. Among the 3,102 patients, 98 (3%) had laboratory-confirmed influenza, of whom, 85 (87%) had ILI and 13 (13%) had SARI. Among ILI patients, the highest proportion of laboratory-confirmed influenza occurred in children less than 5 years of age (3/169; 2% during 2007-2008 and 23/271; 9% during 2008-2009) and patients 25-59 years of age (8/440; 2% during 2007-2009 and 21/483; 4% during 2008-2009). All SARI patients with influenza were less than 14 years of age. During all surveillance years, influenza virus circulation was seasonal with peak circulation during the winter months of October through April.Influenza results in both mild and severe respiratory infections in Morocco, and accounted for a large proportion of all hospitalizations for severe respiratory illness among children 5 years of age and younger

Etude expérimentale du mécanisme néphrotoxique du tacrolimus et des effets pharmacodynamiques de ses métabolites

Tacrolimus is calcineurin inhibitor with immunosuppressive properties widely used for the treatment of transplant patients and patients suffering from autoimmune diseases. It is characterized by very large inter-individual variability and serious adverse effects such as nephrotoxicity, the origins of which remain poorly understood. This work is divided into two main axes. The first one explored the mechanism of tacrolimus nephrotoxicity on a LLC-PK1 renal tubular cell line using combined proteomics and metabolomics analyses. The second investigated the structure of tacrolimus metabolites by high resolution mass spectrometry and studied their 12-hour pharmacokinetic profiles in two groups of renal transplant patients, poor and extensive metabolizers, as well as their impact on the immunosuppressive effect of tacrolimus. This translational research showed that tacrolimus is able to impact different metabolic pathways in proximal tubular cells, such as energy metabolism and gluconeogenesis. Furthermore, it provides for the first-time experimental results suggesting that tacrolimus metabolites are able to decrease the immunosuppressive activity of tacrolimus through a pharmacodynamic interaction.Le tacrolimus est un immunosuppresseur de la famille des inhibiteurs de la calcineurine largement utilisé pour le traitement des patients transplantés ou souffrant de maladies autoimmunes. Le tacrolimus est caractérisé par une très forte variabilité interindividuelle et un risque d’effets indésirables graves, tels qu’une néphrotoxicité, dont les origines restent mal comprises. Ce travail se divise en deux axes principaux. Le premier a exploré le mécanisme de néphrotoxicité du tacrolimus sur la lignée cellulaire tubulaire LLC-PK1, par une double approche protéomique et métabolomique. Le deuxième a investigué la structure des métabolites du tacrolimus par spectrométrie de masse haute résolution et étudié leurs profils pharmacocinétiques chez des patients transplantés rénaux métaboliseurs lents ou rapides, ainsi que leur impact sur l’effet immunosuppresseur du tacrolimus. Cette recherche translationnelle a montré que le tacrolimus modifie différentes voies métaboliques des cellules tubulaires proximales, tels que le métabolisme énergétique et la gluconéogenèse et apporte pour la première fois des résultats expérimentaux suggérant que les métabolites du tacrolimus sont capables de diminuer l’activité immunosuppressive du tacrolimus par une interaction pharmacodynamique

Etude expérimentale du mécanisme néphrotoxique du tacrolimus et des effets pharmacodynamiques de ses métabolites

Tacrolimus is calcineurin inhibitor with immunosuppressive properties widely used for the treatment of transplant patients and patients suffering from autoimmune diseases. It is characterized by very large inter-individual variability and serious adverse effects such as nephrotoxicity, the origins of which remain poorly understood. This work is divided into two main axes. The first one explored the mechanism of tacrolimus nephrotoxicity on a LLC-PK1 renal tubular cell line using combined proteomics and metabolomics analyses. The second investigated the structure of tacrolimus metabolites by high resolution mass spectrometry and studied their 12-hour pharmacokinetic profiles in two groups of renal transplant patients, poor and extensive metabolizers, as well as their impact on the immunosuppressive effect of tacrolimus. This translational research showed that tacrolimus is able to impact different metabolic pathways in proximal tubular cells, such as energy metabolism and gluconeogenesis. Furthermore, it provides for the first-time experimental results suggesting that tacrolimus metabolites are able to decrease the immunosuppressive activity of tacrolimus through a pharmacodynamic interaction.Le tacrolimus est un immunosuppresseur de la famille des inhibiteurs de la calcineurine largement utilisé pour le traitement des patients transplantés ou souffrant de maladies autoimmunes. Le tacrolimus est caractérisé par une très forte variabilité interindividuelle et un risque d’effets indésirables graves, tels qu’une néphrotoxicité, dont les origines restent mal comprises. Ce travail se divise en deux axes principaux. Le premier a exploré le mécanisme de néphrotoxicité du tacrolimus sur la lignée cellulaire tubulaire LLC-PK1, par une double approche protéomique et métabolomique. Le deuxième a investigué la structure des métabolites du tacrolimus par spectrométrie de masse haute résolution et étudié leurs profils pharmacocinétiques chez des patients transplantés rénaux métaboliseurs lents ou rapides, ainsi que leur impact sur l’effet immunosuppresseur du tacrolimus. Cette recherche translationnelle a montré que le tacrolimus modifie différentes voies métaboliques des cellules tubulaires proximales, tels que le métabolisme énergétique et la gluconéogenèse et apporte pour la première fois des résultats expérimentaux suggérant que les métabolites du tacrolimus sont capables de diminuer l’activité immunosuppressive du tacrolimus par une interaction pharmacodynamique

Experimental study of tacrolimus nephrotoxic mechanism and the pharmacodynamic effects of its metabolites

Le tacrolimus est un immunosuppresseur de la famille des inhibiteurs de la calcineurine largement utilisé pour le traitement des patients transplantés ou souffrant de maladies autoimmunes. Le tacrolimus est caractérisé par une très forte variabilité interindividuelle et un risque d’effets indésirables graves, tels qu’une néphrotoxicité, dont les origines restent mal comprises. Ce travail se divise en deux axes principaux. Le premier a exploré le mécanisme de néphrotoxicité du tacrolimus sur la lignée cellulaire tubulaire LLC-PK1, par une double approche protéomique et métabolomique. Le deuxième a investigué la structure des métabolites du tacrolimus par spectrométrie de masse haute résolution et étudié leurs profils pharmacocinétiques chez des patients transplantés rénaux métaboliseurs lents ou rapides, ainsi que leur impact sur l’effet immunosuppresseur du tacrolimus. Cette recherche translationnelle a montré que le tacrolimus modifie différentes voies métaboliques des cellules tubulaires proximales, tels que le métabolisme énergétique et la gluconéogenèse et apporte pour la première fois des résultats expérimentaux suggérant que les métabolites du tacrolimus sont capables de diminuer l’activité immunosuppressive du tacrolimus par une interaction pharmacodynamique.Tacrolimus is calcineurin inhibitor with immunosuppressive properties widely used for the treatment of transplant patients and patients suffering from autoimmune diseases. It is characterized by very large inter-individual variability and serious adverse effects such as nephrotoxicity, the origins of which remain poorly understood. This work is divided into two main axes. The first one explored the mechanism of tacrolimus nephrotoxicity on a LLC-PK1 renal tubular cell line using combined proteomics and metabolomics analyses. The second investigated the structure of tacrolimus metabolites by high resolution mass spectrometry and studied their 12-hour pharmacokinetic profiles in two groups of renal transplant patients, poor and extensive metabolizers, as well as their impact on the immunosuppressive effect of tacrolimus. This translational research showed that tacrolimus is able to impact different metabolic pathways in proximal tubular cells, such as energy metabolism and gluconeogenesis. Furthermore, it provides for the first-time experimental results suggesting that tacrolimus metabolites are able to decrease the immunosuppressive activity of tacrolimus through a pharmacodynamic interaction

Localized Pigmented Villonodular Synovitis of the Posterior Knee Compartment with Popliteal Vessel Compression: A Case Report of Arthroscopic Resection Using Only Anterior Knee Portals

Background. Pigmented villonodular synovitis is a rare pathology causing hyperplasia of the synovium. It mostly affects young populations and most commonly the knee joint. It rarely affects the posterior compartment of the knee as the case presented in this study. Open surgery is usually used to treat this condition; however, in our case it was excised arthroscopically despite the anatomical challenges of the posterior knee compartment. Case Presentation. This case presents a female patient with a complaint of posterior-region pain of her left knee post direct trauma post fall. This was directly followed by knee joint blockage for 1-week duration before presentation to the hospital. On MRI, she was found to have a multiloculated hemosiderin-containing structure of synovial origin within the femoral notch, extending beyond the joint capsule displacing the popliteal vessels. The patient underwent arthroscopic resection of the lesion, which was found to be pigmented villonodular synovitis on anatomopathological examination. On 6-month follow-up, the patient showed good clinical evolution with the absence of symptoms and back-to-normal daily activities. Conclusion. This is a rare case of PVNS affecting the posterior knee joint compartment of a middle-aged woman, which was successfully excised arthroscopically, with no residual affected tissue or recurrence on 6-month follow-up