LES PANCREATITES MEDICAMENTEUSES DIFFICULTES DIAGNOSTIQUES ET THERAPEUTIQUES

Les pancréatites médicamenteuses sont rares mais potentiellement graves. Plusieurs médicaments sont incriminés. Le diagnostic positif repose sur l’établissement d’un lien entre le médicament et la pancréatite aiguë et sur la consultation des centres de pharmacovigilance et des revues de la littérature. Le but de notre travail est de rappeler les différentes étapes du diagnostic et d’insister sur l’importance de la pharmacovigilance. La difficulté diagnostique réside dans le fait que les manifestations cliniques des pancréatites médicamenteuses sont peu spécifiques. De plus, le lien entre un médicament et la survenue d’une pancréatite médicamenteuse peut être difficile à établir. Il repose sur plusieurs critères : sémiologiques, chronologiques et bibliographiques.Une liste de médicaments de plus en plus étendue est mise en cause. Cette liste ne saurait être exhaustive car chaque jour, de nouvelles molécules sont signalées aux centres de pharmacovigilance. La prise en charge des pancréatites médicamenteuses comprend un volet symptomatique mais aussi un volet étiologique qui consiste en un arrêt immédiat du médicament en cause.The drug-induced pancreatitis are rare but potentially serious. Several drugs are accused. The positive diagnosis rests on: - Establishment of a bond between the drug and the acute pancreatitis. -Consultation of centers of pharmacovigilance and reviews of literature. The aim of our work is to point out the various stages of the diagnosis and to insist on the importance of the pharmacovigilance. The diagnostic difficulty lies in the fact that the clinical demonstrations of the drug-induced pancreatitis are not very specific. Moreover, the bond between a drug and occurred of a drug-induced pancreatitis can be difficult to establish.  It rests on several criteria: semiological, chronological and bibliographical. Un increasingly wide list of drugs is blamed. This list could not be exhaustive because each day, of new molecules are announced to the centers of pharmacovigilance. The assumption of responsibility of the drug-induced pancreatitis comprises a symptomatic aspect but also a shutter etiologic which consists of a dead halt of the drug in question

Quantification of ciprofloxacin in pharmaceutical products from various brands using FT-NIR: A comparative investigation of PLS and MCR-ALS.

peer reviewedThis study aims to quantify ciprofloxacin in commercial tablets with varying excipient compositions using Fourier Transform Near-Infrared Spectroscopy (FT-NIR) and chemometric models: Partial Least Squares (PLS) and Multivariate Curve Resolution - Alternating Least Squares (MCR-ALS). Matrix variation, arising from differences in excipient compositions among the tablets, can impact quantification accuracy. We discuss this phenomenon, emphasizing potential issues introduced by varying certain excipients and its importance in reliable ciprofloxacin quantification. We evaluated the performance of PLS and MCR-ALS models independently on two sets of tablets, each containing the same drug substance but different excipients. The statistical results revealed promising results with PLS prediction error of 0.38% w/w of the first set and 0.47% w/w of the second set, while MCR-ALS achieved prediction errors of 0.67% w/w of the first set and 1.76% w/w of the second set. To address the challenge of matrix variation, we developed single models for PLS and MCR-ALS using a dataset combining both first and second sets. The PLS single model demonstrated a prediction error of 4.3% w/w and a relative error of 6.41% w/w, while the MCR-ALS single model showed a prediction error of 1.88% w/w and a relative error of 1.29% w/w. We then assessed the performance of the single PLS and MCR-ALS models developed based on the combination of the first and the second set in quantifying ciprofloxacin in various commercial tablet brands containing new excipients. The PLS model achieved a prediction error ranging between 6.2% w/w and 8.39% w/w, with relative errors varied between 8.53% w/w and 12.82% w/w. On the other hand, the MCR-ALS model had a prediction error between 1.11% w/w and 2.66% w/w, and the relative errors ranging from 0.8% to 1.74% w/w

Accelerated expansion from structure formation

We discuss the physics of backreaction-driven accelerated expansion. Using the exact equations for the behaviour of averages in dust universes, we explain how large-scale smoothness does not imply that the effect of inhomogeneity and anisotropy on the expansion rate is small. We demonstrate with an analytical toy model how gravitational collapse can lead to acceleration. We find that the conjecture of the accelerated expansion being due to structure formation is in agreement with the general observational picture of structures in the universe, and more quantitative work is needed to make a detailed comparison.Comment: 44 pages, 1 figure. Expanded treatment of topics from the Gravity Research Foundation contest essay astro-ph/0605632. v2: Added references, clarified wordings. v3: Published version. Minor changes and corrections, added a referenc

IL-12Rβ1 Deficiency in Two of Fifty Children with Severe Tuberculosis from Iran, Morocco, and Turkey

BACKGROUND AND OBJECTIVES: In the last decade, autosomal recessive IL-12Rβ1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rβ1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common. METHODS AND PRINCIPAL FINDINGS: We searched for IL12RB1 mutations in a series of 50 children from Iran, Morocco, and Turkey. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from Iran and another from Morocco, homozygosity for loss-of-function IL12RB1 alleles was documented, resulting in complete IL-12Rβ1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rβ1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease. SIGNIFICANCE: This finding may have important medical implications, as recombinant IFN-γ is an effective treatment for mycobacterial infections in IL-12Rβ1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity

α5β1 Integrin-Mediated Adhesion to Fibronectin Is Required for Axis Elongation and Somitogenesis in Mice

The arginine-glycine-aspartate (RGD) motif in fibronectin (FN) represents the major binding site for α5β1 and αvβ3 integrins. Mice lacking a functional RGD motif in FN (FNRGE/RGE) or α5 integrin develop identical phenotypes characterized by embryonic lethality and a severely shortened posterior trunk with kinked neural tubes. Here we show that the FNRGE/RGE embryos arrest both segmentation and axis elongation. The arrest is evident at about E9.0, corresponding to a stage when gastrulation ceases and the tail bud-derived presomitic mesoderm (PSM) induces α5 integrin expression and assumes axis elongation. At this stage cells of the posterior part of the PSM in wild type embryos are tightly coordinated, express somitic oscillator and cyclic genes required for segmentation, and form a tapered tail bud that extends caudally. In contrast, the posterior PSM cells in FNRGE/RGE embryos lost their tight associations, formed a blunt tail bud unable to extend the body axis, failed to induce the synchronised expression of Notch1 and cyclic genes and cease the formation of new somites. Mechanistically, the interaction of PSM cells with the RGD motif of FN is required for dynamic formation of lamellipodia allowing motility and cell-cell contact formation, as these processes fail when wild type PSM cells are seeded into a FN matrix derived from FNRGE/RGE fibroblasts. Thus, α5β1-mediated adhesion to FN in the PSM regulates the dynamics of membrane protrusions and cell-to-cell communication essential for elongation and segmentation of the body axis

Low Levels of Human HIP14 Are Sufficient to Rescue Neuropathological, Behavioural, and Enzymatic Defects Due to Loss of Murine HIP14 in Hip14−/− Mice

Huntingtin Interacting Protein 14 (HIP14) is a palmitoyl acyl transferase (PAT) that was first identified due to altered interaction with mutant huntingtin, the protein responsible for Huntington Disease (HD). HIP14 palmitoylates a specific set of neuronal substrates critical at the synapse, and downregulation of HIP14 by siRNA in vitro results in increased cell death in neurons. We previously reported that mice lacking murine Hip14 (Hip14−/−) share features of HD. In the current study, we have generated human HIP14 BAC transgenic mice and crossed them to the Hip14−/− model in order to confirm that the defects seen in Hip14−/− mice are in fact due to loss of Hip14. In addition, we sought to determine whether human HIP14 can provide functional compensation for loss of murine Hip14. We demonstrate that despite a relative low level of expression, as assessed via Western blot, BAC-derived human HIP14 compensates for deficits in neuropathology, behavior, and PAT enzyme function seen in the Hip14−/− model. Our findings yield important insights into HIP14 function in vivo

Palmitoylation Regulates Epidermal Homeostasis and Hair Follicle Differentiation

Palmitoylation is a key post-translational modification mediated by a family of DHHC-containing palmitoyl acyl-transferases (PATs). Unlike other lipid modifications, palmitoylation is reversible and thus often regulates dynamic protein interactions. We find that the mouse hair loss mutant, depilated, (dep) is due to a single amino acid deletion in the PAT, Zdhhc21, resulting in protein mislocalization and loss of palmitoylation activity. We examined expression of Zdhhc21 protein in skin and find it restricted to specific hair lineages. Loss of Zdhhc21 function results in delayed hair shaft differentiation, at the site of expression of the gene, but also leads to hyperplasia of the interfollicular epidermis (IFE) and sebaceous glands, distant from the expression site. The specific delay in follicle differentiation is associated with attenuated anagen propagation and is reflected by decreased levels of Lef1, nuclear β-catenin, and Foxn1 in hair shaft progenitors. In the thickened basal compartment of mutant IFE, phospho-ERK and cell proliferation are increased, suggesting increased signaling through EGFR or integrin-related receptors, with a parallel reduction in expression of the key differentiation factor Gata3. We show that the Src-family kinase, Fyn, involved in keratinocyte differentiation, is a direct palmitoylation target of Zdhhc21 and is mislocalized in mutant follicles. This study is the first to demonstrate a key role for palmitoylation in regulating developmental signals in mammalian tissue homeostasis

A Strawberry KNOX Gene Regulates Leaf, Flower and Meristem Architecture

The KNOTTED-LIKE HOMEODOMAIN (KNOX) genes play a central role in maintenance of the shoot apical meristem. They also contribute to the morphology of simple and compound leaves. In this report we characterize the FaKNOX1 gene from strawberry (Fragaria spp.) and demonstrate its function in trasgenic plants. The FaKNOX1 cDNA was isolated from a cultivated strawberry (F.×ananassa) flower EST library. The sequence is most similar to Class I KNOX genes, and was mapped to linkage group VI of the diploid strawberry genome. Unlike most KNOX genes studied, steady-state transcript levels were highest in flowers and fruits. Transcripts were also detected in emerging leaf primordia and the apical dome. Transgenic strawberry plants suppressing or overexpressing FaKNOX1 exhibited conspicuous changes in plant form. The FaKNOX1 RNAi plants presented a dwarfed phenotype with deeply serrated leaflets and exaggerated petiolules. They also exhibited a high level of cellular disorganization of the shoot apical meristem and leaves. Overexpression of FaKNOX1 caused dwarfed stature with wrinkled leaves. These gain- and loss-of-function assays in strawberry functionally demonstrate the contributions of a KNOX domain protein in a rosaceous species