Advanced nanostructured medical device combining mesenchymal cells and VEGF nanoparticles for enhanced engineered tissue vascularization.

AIM: Success of functional vascularized tissue repair depends on vascular support system supply and still remains challenging. Our objective was to develop a nanoactive implant enhancing endothelial cell activity, particularly for bone tissue engineering in the regenerative medicine field. MATERIALS & METHODS: We developed a new strategy of tridimensional implant based on cell-dependent sustained release of VEGF nanoparticles. These nanoparticles were homogeneously distributed within nanoreservoirs onto the porous scaffold, with quicker reorganization of endothelial cells. Moreover, the activity of this active smart implant on cells was also modulated by addition of osteoblastic cells. RESULTS & CONCLUSION: This sophisticated active strategy should potentiate efficiency of current therapeutic implants for bone repair, avoiding the need for bone substitutes

Can Valproic Acid be an Inducer of Clozapine Metabolism?

Introduction: Prior clozapine studies indicated no effects, mild inhibition or induction of valproic acid (VPA) on clozapine metabolism. The hypotheses that (i) VPA is a net inducer of clozapine metabolism, and (ii) smoking modifies this inductive effect were tested in a therapeutic drug monitoring study. Methods: After excluding strong inhibitors and inducers, 353 steady-state total clozapine (clozapine plus norclozapine) concentrations provided by 151 patients were analyzed using a random intercept linear model. Results: VPA appeared to be an inducer of clozapine metabolism since total plasma clozapine concentrations in subjects taking VPA were significantly lower (27% lower; 95% confidence interval, 14-39%) after controlling for confounding variables including smoking (35% lower, 28-56%). Discussion: Prospective studies are needed to definitively establish that VPA may (i) be an inducer of clozapine metabolism when induction prevails over competitive inhibition, and (ii) be an inducer even in smokers who are under the influence of smoking inductive effects on clozapine metabolism

Anterior minimally invasive extrapleural retroperitoneal approach to the thoraco-lumbar junction of the spine

SummaryBackgroundThe anterior approach to the thoraco-lumbar junction of the spine allows therapeutic interventions on post-traumatic, infectious, and neoplastic vertebral lesions from T11 to L2 combining spinal cord decompression, corporectomy, and vertebral body fusion. However, this approach also has a reputation for damaging the intervening anatomic structures (lungs, peritoneum, and diaphragm). The objective of this study was to show that both nervous structure decompression and anterior vertebral reconstruction can be achieved via an anterior minimally invasive extrapleural retroperitoneal (AMIER) approach.MaterialWe describe each of the steps of the AMIER approach to the thoraco-lumbar junction of the spine.ResultsThe AMIER approach ensures excellent exposure that allows full decompression and satisfactory anterior anatomic reconstruction. The main difficulties and complications relate to the lungs, and a painstaking and rigorous technique limits the complications compared to conventional thoraco-phreno-lumbotomy

Nanoengineered implant as a new platform for regenerative nanomedicine using 3D well-organized human cell spheroids

In tissue engineering, it is still rare today to see clinically transferable strategies for tissue-engineered graft production that conclusively offer better tissue regeneration than the already existing technologies, decreased recovery times, and less risk of complications. Here a novel tissue-engineering concept is presented for the production of living bone implants combining 1) a nanofibrous and microporous implant as cell colonization matrix and 2) 3D bone cell spheroids. This combination, double 3D implants, shows clinical relevant thicknesses for the treatment of an early stage of bone lesions before the need of bone substitutes. The strategy presented here shows a complete closure of a defect in nude mice calvaria after only 31 days. As a novel strategy for bone regenerative nanomedicine, it holds great promises to enhance the therapeutic efficacy of living bone implants

Associations of maternal obesity and excessive weight gain during pregnancy with subcutaneous fat mass in infancy

Background: Not much is known about the associations of maternal obesity and excessive gestational weight gain with body fat in infancy. Objective: To examine the associations of maternal pre-pregnancy body mass index and gestational weight gain with infant subcutaneous fat. Methods: In a population-based prospective cohort study among 845 mothers and their infants, we obtained maternal pre-pregnancy body mass index and measured maternal weight during pregnancy. At 1.5, 6 and 24 months, we estimated infant total subcutaneous fat (sum of biceps, triceps, suprailiacal and subscapular skinfold thicknesses) and central-to-total subcutaneous fat ratio (sum of suprailiacal and subscapular skinfold thicknesses/total subcutaneous fat). Results: Maternal body mass index was positively associated with higher infant body mass index from 6 months onwards. Maternal body mass index was not associated with infant subcutaneous fat measures at 1.5 or 6 months. A 1-standard deviation scores (SDS) higher maternal body mass index was associated with a 0.09 (95% Confidence Interval 0.01, 0.17) SDS higher infant total subcutaneous fat at 24 months, but not with central-to-total subcutaneous fat ratio. No associations were present for maternal total or period-specific gestational weight gain with infant fat. Conclusion: Maternal body mass index was positively associated with infant body mass index and total subcutaneous fat in late infancy. Maternal total and period-specific gestational weight gain were not associated with infant body fat mass measures.The general design of the Generation R Study is made possible by financial support from the Erasmus MC, University Medical Center, Rotterdam, Erasmus University Rotterdam, Netherlands Organization for Health Research and Development (ZonMw), Netherlands Organisation for Scientific Research (NWO), Ministry of Health, Welfare and Sport and Ministry of Youth and Families. Research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013), project EarlyNutrition under grant agreement n°289346. Susana Santos received a grant from the Portuguese Foundation for Science and Technology (SFRH/BD/81123/2011). Vincent Jaddoe received an additional grant from the Netherlands Organization for Health Research and Development (NWO, ZonMw-VIDI 016.136.361) and Consolidator Grant from the European research Council (ERC-2014-CoG-648916)

Prospective assessment of CYP2D6 by genotyping, phenotyping and measurement of tamoxifen, PD 05-09 4-hydroxy-tamoxifen and endoxifen in breast cancer patients treated with tamoxifen.

Tamoxifen (tam) is a widely used endocrine therapy in the treatment of early and advanced stage breast cancer in women and men. It is a pro-drug having weak affinity with the estrogen receptor and needs to be converted to its main metabolite, endoxifen (endox), to have full anticancer activity. Cytochrome 2D6 (CYP2D6) plays a major role in the metabolism of tamoxifen to endoxifen. It is genetically highly polymorphic and its activity influences profoundly the synthesis of endoxifen and potentially the efficacy of tamoxifen treatment. Genotyping is currently the most widely used approach in studies and also in clinical practice to categorize patients as poor- (PM), intermediate- (IM), extensive- (EM) and ultra rapid-metabolizers (UM). Some clinicians already use genotyping in order to tailor the endocrine therapy of their patients. Owing to the large inter-individual variations in concentrations of the active moitey due to genetic and non-genetic influences renders the predictive value of the test uncertain for an individual patient. A significant number of patients classified as EM or IM by genotyping have indeed relatively low endoxifen levels similar to PMs1. This suggests that genotyping is probably not the opti ma l meth o d f or predi cti ng end oxif en l evels

A living thick nanofibrous implant bifunctionalized with active growth factor and stem cells for bone regeneration

New-generation implants focus on robust, durable, and rapid tissue regeneration to shorten recovery times and decrease risks of postoperative complications for patients. Herein, we describe a new-generation thick nanofibrous implant functionalized with active containers of growth factors and stem cells for regenerative nanomedicine. A thick electrospun poly(e- caprolactone) nanofibrous implant (from 700 µm to 1 cm thick) was functionalized with chitosan and bone morphogenetic protein BMP-7 as growth factor using layer-by-layer technology, producing fish scale-like chitosan/BMP-7 nanoreservoirs. This extracellular matrix-mimicking scaffold enabled in vitro colonization and bone regeneration by human primary osteoblasts, as shown by expression of osteocalcin, osteopontin, and bone sialoprotein (BSPII), 21 days after seeding. In vivo implantation in mouse calvaria defects showed significantly more newly mineralized extracellular matrix in the functionalized implant compared to a bare scaffold after 30 days’ implantation, as shown by histological scanning electron microscopy/energy dispersive X-ray microscopy study and calcein injection. We have as well bifunctionalized our BMP-7 therapeutic implant by adding human mesenchymal stem cells (hMSCs). The activity of this BMP-7-functionalized implant was again further enhanced by the addition of hMSCs to the implant (living materials), in vivo, as demonstrated by the analysis of new bone formation and calcification after 30 days’ implantation in mice with calvaria defects. Therefore, implants functionalized with BMP-7 nanocontainers associated with hMSCs can act as an accelerator of in vivo bone mineralization and regeneration

Prediction of early weight gain during psychotropic treatment using a combinatorial model with clinical and genetic markers.

Psychotropic drugs can induce significant (>5%) weight gain (WG) already after 1 month of treatment, which is a good predictor for major WG at 3 and 12 months. The large interindividual variability of drug-induced WG can be explained in part by genetic and clinical factors. The aim of this study was to determine whether extensive analysis of genes, in addition to clinical factors, can improve prediction of patients at risk for more than 5% WG at 1 month of treatment. Data were obtained from a 1-year naturalistic longitudinal study, with weight monitoring during weight-inducing psychotropic treatment. A total of 248 Caucasian psychiatric patients, with at least baseline and 1-month weight measures, and with compliance ascertained were included. Results were tested for replication in a second cohort including 32 patients. Age and baseline BMI were associated significantly with strong WG. The area under the curve (AUC) of the final model including genetic (18 genes) and clinical variables was significantly greater than that of the model including clinical variables only (AUCfinal: 0.92, AUCclinical: 0.75, P<0.0001). Predicted accuracy increased by 17% with genetic markers (Accuracyfinal: 87%), indicating that six patients must be genotyped to avoid one misclassified patient. The validity of the final model was confirmed in a replication cohort. Patients predicted before treatment as having more than 5% WG after 1 month of treatment had 4.4% more WG over 1 year than patients predicted to have up to 5% WG (P≤0.0001). These results may help to implement genetic testing before starting psychotropic drug treatment to identify patients at risk of important WG

Association of ABCB1 genetic variants with renal function in Africans and in Caucasians.

ABSTRACT: BACKGROUND: The P-glycoprotein, encoded by the ABCB1 gene, is expressed in human endothelial and mesangial cells, which contribute to control renal plasma flow and glomerular filtration rate. We investigated the association of ABCB1 variants with renal function in African and Caucasian subjects. METHODS: In Africans (290 subjects from 62 pedigrees), we genotyped the 2677G>T and 3435 C>T ABCB1 polymorphisms. Glomerular filtration rate (GFR) was measured using inulin clearance and effective renal plasma flow (ERPF) using para-aminohippurate clearance. In Caucasians (5382 unrelated subjects), we analyzed 30 SNPs located within and around ABCB1, using data from the Affymetrix 500 K chip. GFR was estimated using the simplified Modification of the Diet in Renal Disease (MDRD) and Cockcroft-Gault equations. RESULTS: In Africans, compared to the reference genotype (GG or CC), each copy of the 2677T and 3435T allele was associated, respectively, with: GFR higher by 10.6 +/- 2.9 (P < 0.001) and 4.4 +/- 2.3 (P = 0.06) mL/min; ERPF higher by 47.5 +/- 11.6 (P < 0.001) and 28.1 +/- 10.5 (P = 0.007) mL/min; and renal resistances lower by 0.016 +/- 0.004 (P < 0.001) and 0.011 +/- 0.004 (P = 0.004) mm Hg/mL/min. In Caucasians, we identified 3 polymorphisms in the ABCB1 gene that were strongly associated with all estimates of GFR (smallest P value = 0.0006, overall P = 0.014 after multiple testing correction). CONCLUSION: Variants of the ABCB1 gene were associated with renal function in both Africans and Caucasians and may therefore confer susceptibility to nephropathy in humans. If confirmed in other studies, these results point toward a new candidate gene for nephropathy in humans