A partially demineralized allogeneic bone graft: in vitro osteogenic potential and preclinical evaluation in two different intramembranous bone healing models.

In skeletal surgical procedures, bone regeneration in irregular and hard-to-reach areas may present clinical challenges. In order to overcome the limitations of traditional autologous bone grafts and bone substitutes, an extrudable and easy-to-handle innovative partially demineralized allogenic bone graft in the form of a paste has been developed. In this study, the regenerative potential of this paste was assessed and compared to its clinically used precursor form allogenic bone particles. Compared to the particular bone graft, the bone paste allowed better attachment of human mesenchymal stromal cells and their commitment towards the osteoblastic lineage, and it induced a pro-regenerative phenotype of human monocytes/macrophages. The bone paste also supported bone healing in vivo in a guide bone regeneration model and, more interestingly, exhibited a substantial bone-forming ability when implanted in a critical-size defect model in rat calvaria. Thus, these findings indicate that this novel partially demineralized allogeneic bone paste that combines substantial bone healing properties and rapid and ease-of-use may be a promising alternative to allogeneic bone grafts for bone regeneration in several clinical contexts of oral and maxillofacial bone grafting.

Controlled release of biological factors for endogenous progenitor cell migration and intervertebral disc extracellular matrix remodelling.

The recent description of resident stem/progenitor cells in degenerated intervertebral discs (IVDs) supports the notion that their regenerative capacities could be harnessed to stimulate endogenous repair of the nucleus pulposus (NP). In this study, we developed a delivery system based on pullulan microbeads (PMBs) for sequential release of the chemokine CCL-5 to recruit these disc stem/progenitor cells to the NP tissue, followed by the release of the growth factors TGF-ß1 and GDF-5 to induce the synthesis of a collagen type II- and aggrecan-rich extracellular matrix (ECM). Bioactivity of released CCL5 on human adipose-derived stem cells (hASCs), selected to mimic disc stem/progenitors, was demonstrated using a Transwell® chemotaxis assay. The regenerative effects of loaded PMBs were investigated in ex vivo spontaneously degenerated ovine IVDs. Fluorescent hASCs were seeded on the top cartilaginous endplates (CEPs); the degenerated NPs were injected with PMBs loaded with CCL5, TGF-ß1, and GDF-5; and the IVDs were then cultured for 3, 7, and 28 days to allow for cell migration and disc regeneration. The PMBs exhibited sustained release of biological factors for 21 days. Ex vivo migration of seeded hASCs from the CEP toward the NP was demonstrated, with the cells migrating a significantly greater distance when loaded PMBs were injected (5.8 ± 1.3 mm vs. 3.5 ± 1.8 mm with no injection of PMBs). In ovine IVDs, the overall NP cellularity, the collagen type II and the aggrecan staining intensities, and the Tie2+ progenitor cell density in the NP were increased at day 28 compared to the control groups. Considered together, PMBs loaded with CCL5/TGF-ß1/GDF-5 constitute an innovative and promising strategy for controlled release of growth factors to promote cell recruitment and extracellular matrix remodelling.

Synthesis and reactivity of N,N'-1,4-diazabutadiene derived borocations.

A series of borocations have been synthesised from the addition of haloboranes to synthetically accessible N,N'-1,4-diazabutadiene precursors, which are derived from commercially available anilines. The synthesis and structural studies of the borocations are described.

Antidepressant treatment patterns in younger and older adults from the general population in a real-life setting.

OBJECTIVE: The treatment of depression in real-life settings appears to be influenced by health care systems. Antidepressant drugs have been found to be underused in the older population relative to younger adults when refunding of such drugs is poor. No study assessed the pattern of antidepressant use according to age in a universal health care system. The objective is to assess whether the pattern of antidepressant drug use differs between younger and older adults with respect to treatment duration, adherence to treatment, coprescription of other psychotropic drugs, switch, or combination of antidepressant drugs. METHODS: A historical cohort study included 7747 older (65+ years) and 27,306 younger (younger than 65 years) adults representative of the beneficiaries of the French national health care insurance system who initiated a new antidepressant treatment. Follow-up after treatment initiation was at least 6 months. RESULTS: Older patients had a significantly longer duration of treatment than younger adults (hazard ratio = 0.90; 95%CI[0.88-0.93]). Adherence was more often good in older than in younger adults when the treatment was initiated by a general practitioner (23.4% vs. 16.7%; Odds ratio (OR) = 1.35[1.25-1.46]), a hospital practitioner (OR = 1.68[1.40-2.03]) or another specialist (OR = 1.60[1.19-2.17]). The coprescription of psychotropic drugs decreased with older age in men (OR = 0.77[0.70-0.85]) and increased with older age in women (OR = 1.14[1.07-1.22]). Switches and combinations of antidepressants were not associated with age. CONCLUSION: In a universal health care system, with similar reimbursement of drugs regardless of age, treatment duration, and adherence were better in the older patients than in the younger ones.

Comparison of three methods (an updated logistic probabilistic method, the Naranjo and Liverpool algorithms) for the evaluation of routine pharmacovigilance case reports using consensual expert judgement as reference.

BACKGROUND: An updated probabilistic causality assessment method and the Liverpool algorithm presented as an improved version of the Naranjo algorithm, one of the most used and accepted causality assessment methods, have recently been proposed. OBJECTIVE: In order to test the validity of the probabilistic method in routine pharmacovigilance, results provided by the Naranjo and Liverpool algorithms, as well as the updated probabilistic method, were each compared with a consensual expert judgement taken as reference. METHODS: A sample of 59 drug-event pairs randomly sampled from spontaneous reports to the French pharmacovigilance system was assessed by expert judgement until reaching consensus and by members of a pharmacovigilance unit using the updated probabilistic method, the Naranjo and Liverpool algorithms. Probabilities given by the probabilistic method, and categories obtained by both the Naranjo and the Liverpool algorithms were compared as well as their sensitivity, specificity, positive and negative predictive values. RESULTS: The median probability for drug causation given by the consensual expert judgement was 0.70 (inter-quartile range, IQR 0.54-0.84) versus 0.77 (IQR 0.54-0.91) for the probabilistic method. For the Naranjo algorithm, the 'possible' causality category was predominant (61 %), followed by 'probable' (35 %), 'doubtful', and 'almost certain' categories (2 % each). Category distribution obtained with the Liverpool algorithm was similar to that obtained by the Naranjo algorithm with a majority of 'possible' (61 %) and 'probable' (30 %) followed by 'definite' (7 %) and 'unlikely' (2 %). For the probabilistic method, sensitivity, specificity, positive and negative predictive values were 0.96, 0.56, 0.92 and 0.71, respectively. For the Naranjo algorithm, depending on whether the 'possible' category was considered in favour or in disfavour of drug causation, sensitivity was, respectively, 1 or 0.42, specificity 0.11 or 0.89, negative predictive value 1 or 0.22 and positive predictive value 0.86 or 0.95; results were identical for the Liverpool algorithm. CONCLUSION: The logistic probabilistic method gave results closer to the consensual expert judgment than either the Naranjo or Liverpool algorithms whose performance were strongly dependent on the meaning given to the 'possible' category. Owing to its good sensitivity and positive predictive value and by providing results as continuous probabilities, the probabilistic method seems worthy to use for a trustable assessment of adverse drug reactions in routine practice.

An updated method improved the assessment of adverse drug reaction in routine pharmacovigilance.

OBJECTIVE: Updating a logistic causality assessment method to improve its agreement with consensual expert judgment (CEJ). STUDY DESIGN AND SETTING: A random sample of 53 drug-event pairs from a pharmacovigilance database were evaluated independently by CEJ and by a group of experts in pharmacovigilance using the logistic method. Causes of disagreement between both approaches were analyzed, and changes in the assessment of some criteria of the logistic method were proposed and tested in models. The model giving results closest to the CEJ was retained and compared with the initial version on another set of drug-event pairs. RESULTS: Finally, only the criterion "Search for nondrug cause" was changed into "Search for other causes." The assessment not investigated, possible other cause decreased the probability of drug causation instead of being neutral, whereas the assessment not applicable, not required remained neutral. This new version presents much improved specificity (0.56 vs. 0.33), relatively good sensitivity (0.96), and positive and negative predictive values (0.92 and 0.71). CONCLUSION: The updated logistic method presented here improves the initial version that had poor specificity and tended to overestimate drug causation. This new version presents satisfactory characteristics to be used in routine pharmacovigilance.