N-methyl pyrrolidone as a potent bone morphogenetic protein enhancer for bone tissue regeneration

In medicine N-methylpyrrolidone (NMP) has a long track record as constituent in FDA approved medical devices and thus can be considered as safe and biological inactive small chemical. In the present study we report on the newly discovered pharmaceutical properties of NMP as it enhances bone regeneration in a rabbit calvarial defect model in vivo. At the cellular level, the pharmaceutical effect of NMP was confirmed, in particular, in combination with BMP-2, as NMP increased early and late markers for maturation of preosteoblasts and human bone marrow derived stem cells in vitro. When we used the multipotent cell line C2C12 lacking autologous BMP expression, NMP alone had no effect on alkaline phosphatase activity, a marker for osteogenic transdifferentiation. Nevertheless, in combination with low BMP-2-doses alkaline phosphatase activity was increased more than 8 fold. Thus, the pharmaceutical NMP mode of action is that of an enhancer of BMP activity. The dependency of the effects of NMP on BMP was confirmed in preosteoblasts as noggin, an extracellular BMP-inhibitor, suppressed NMP-induced increase in early markers for osteoblast maturation in vitro. At the molecular level, NMP was shown to have no effect on the binding of BMP-2 to the ectodomain of the high affinity BMP receptor IA. However, NMP further increased the phosphorylation of p38 and Smad1,5,8 induced by BMP-2. Thus, the small chemical NMP enhances BMP activity by increasing the kinase activity of the BMP receptor complex for Smad1,5,8 and p38 and could be employed as a potent drug for bone tissue regeneration and engineering

Quantum Maxwell-Bloch equations for spatially inhomogeneous semiconductor lasers

We present quantum Maxwell-Bloch equations (QMBE) for spatially inhomogeneous semiconductor laser devices. The QMBE are derived from fully quantum mechanical operator dynamics describing the interaction of the light field with the quantum states of the electrons and the holes near the band gap. By taking into account field-field correlations and field-dipole correlations, the QMBE include quantum noise effects which cause spontaneous emission and amplified spontaneous emission. In particular, the source of spontaneous emission is obtained by factorizing the dipole-dipole correlations into a product of electron and hole densities. The QMBE are formulated for general devices, for edge emitting lasers and for vertical cavity surface emitting lasers, providing a starting point for the detailed analysis of spatial coherence in the near field and far field patterns of such laser diodes. Analytical expressions are given for the spectra of gain and spontaneous emission described by the QMBE. These results are applied to the case of a broad area laser, for which the frequency and carrier density dependent spontaneous emission factor beta and the evolution of the far field pattern near threshold are derived.Comment: 22 pages RevTex and 7 figures, submitted to Phys.Rev.A, revisions in abstract and in the discussion of temporal coherenc

Deterministic polarization chaos from a laser diode

Fifty years after the invention of the laser diode and fourty years after the report of the butterfly effect - i.e. the unpredictability of deterministic chaos, it is said that a laser diode behaves like a damped nonlinear oscillator. Hence no chaos can be generated unless with additional forcing or parameter modulation. Here we report the first counter-example of a free-running laser diode generating chaos. The underlying physics is a nonlinear coupling between two elliptically polarized modes in a vertical-cavity surface-emitting laser. We identify chaos in experimental time-series and show theoretically the bifurcations leading to single- and double-scroll attractors with characteristics similar to Lorenz chaos. The reported polarization chaos resembles at first sight a noise-driven mode hopping but shows opposite statistical properties. Our findings open up new research areas that combine the high speed performances of microcavity lasers with controllable and integrated sources of optical chaos.Comment: 13 pages, 5 figure

Noise induced transition from an absorbing phase to a regime of stochastic spatiotemporal intermittency

We introduce a stochastic partial differential equation capable of reproducing the main features of spatiotemporal intermittency (STI). Additionally the model displays a noise induced transition from laminarity to the STI regime. We show by numerical simulations and a mean-field analysis that for high noise intensities the system globally evolves to a uniform absorbing phase, while for noise intensities below a critical value spatiotemporal intermittence dominates. A quantitative computation of the loci of this transition in the relevant parameter space is presented.Comment: 4 pages, 6 eps figures. Submitted to Phys. Rev. Lett. See for additional information http://imedea.uib.es

Recent results on multiplicative noise

Recent developments in the analysis of Langevin equations with multiplicative noise (MN) are reported. In particular, we: (i) present numerical simulations in three dimensions showing that the MN equation exhibits, like the Kardar-Parisi-Zhang (KPZ) equation both a weak coupling fixed point and a strong coupling phase, supporting the proposed relation between MN and KPZ; (ii) present dimensional, and mean field analysis of the MN equation to compute critical exponents; (iii) show that the phenomenon of the noise induced ordering transition associated with the MN equation appears only in the Stratonovich representation and not in the Ito one, and (iv) report the presence of a new first-order like phase transition at zero spatial coupling, supporting the fact that this is the minimum model for noise induced ordering transitions.Comment: Some improvements respect to the first versio

Exposure-Response and Population Pharmacokinetic Analyses of a Novel Subcutaneous Formulation of Daratumumab Administered to Multiple Myeloma Patients

We report the population pharmacokinetic (PK) and exposure-response analyses of a novel subcutaneous formulation of daratumumab (DARA) using data from 3 DARA subcutaneous monotherapy studies (PAVO Part 2, MMY1008, COLUMBA) and 1 combination therapy study (PLEIADES). Results were based on 5159 PK samples from 742 patients (DARA 1800 mg subcutaneously, n = 487 [monotherapy, n = 288; combination therapy, n = 199]; DARA 16 mg/kg intravenously, n = 255 [all monotherapy, in COLUMBA]; age, 33-92 years; weight, 28.6-147.6 kg). Subcutaneous and intravenous DARA monotherapies were administered once every week for cycles 1-2, once every 2 weeks for cycles 3-6, and once every 4 weeks thereafter (1 cycle is 28 days). The subcutaneous DARA combination therapy was administered with the adaptation of corresponding standard-of-care regimens. PK samples were collected between cycle 1 and cycle 12. Among monotherapy studies, throughout the treatment period, subcutaneous DARA provided similar/slightly higher trough concentrations (Ctrough) versus intravenous DARA, with lower maximum concentrations and smaller peak-to-trough fluctuations. The PK profile was consistent between subcutaneous DARA monotherapy and combination therapies. The exposure-response relationship between daratumumab PK and efficacy or safety end points was similar for subcutaneous and intravenous DARA. Although the ≤65-kg subgroup reported a higher incidence of neutropenia, no relationship was found between the incidence of neutropenia and exposure, which was attributed, in part, to the preexisting imbalance in neutropenia between subcutaneous DARA (45.5%) and intravenous DARA (19%) in patients ≤50 kg. A flat relationship was observed between body weight and any grade and at least grade 3 infections. The results support the DARA 1800-mg subcutaneous flat dose as an alternative to the approved intravenous DARA 16 mg/kg.The clinical studies and the analyses presented here were supported by research funding from Janssen Research & Development, LLC

Polarisation Patterns and Vectorial Defects in Type II Optical Parametric Oscillators

Previous studies of lasers and nonlinear resonators have revealed that the polarisation degree of freedom allows for the formation of polarisation patterns and novel localized structures, such as vectorial defects. Type II optical parametric oscillators are characterised by the fact that the down-converted beams are emitted in orthogonal polarisations. In this paper we show the results of the study of pattern and defect formation and dynamics in a Type II degenerate optical parametric oscillator for which the pump field is not resonated in the cavity. We find that traveling waves are the predominant solutions and that the defects are vectorial dislocations which appear at the boundaries of the regions where traveling waves of different phase or wave-vector orientation are formed. A dislocation is defined by two topological charges, one associated with the phase and another with the wave-vector orientation. We also show how to stabilize a single defect in a realistic experimental situation. The effects of phase mismatch of nonlinear interaction are finally considered.Comment: 38 pages, including 15 figures, LATeX. Related material, including movies, can be obtained from http://www.imedea.uib.es/Nonlinear/research_topics/OPO

Body composition changes during a multidisciplinary treatment programme in overweight adolescents: EVASYON Study

Resumen Introducción: el principal objetivo de las intervenciones de pérdida de peso es disminuir la masa grasa manteniendo la masa libre de grasa. Objetivo: evaluar la efectividad de una intervención multidisciplinar en la composición corporal de adolescentes con sobrepeso, evaluados mediante diferentes métodos de composición corporal. Material y métodos: la intervención fue multidisciplinar sobre el estilo de vida, aplicada durante 13 meses. Los participantes eran adolescentes entre 13 y 16 años con sobrepeso y obesidad. Los adolescentes (n = 156; 54,8% mujeres) fueron evaluados mediante antropometría, absorciometría dual de rayos X y pletismografía por desplazamiento de aire. Todas las mediciones se realizaron al inicio, a los 2 y a los 13 meses. Se aplicaron análisis de la covarianza de medidas repetidas y la corrección de Bonferroni. Se realizó la imputación de las medidas antropométricas. Resultados: se logró una alta disminución significativa en el índice de masa grasa en los hombres después de 2 y 13 meses de intervención, según antropometría (1,16 y 1,56 kg/m2, respectivamente), absorciometría de rayos X (1,51 y 1,91 kg/m2) y pletismografía (2,13 y 2,44 kg/m2). Por otra parte, el mantenimiento a corto y largo plazo de la grasa y libre de grasa en el índice de masa fue observado por absorciometría de rayos X en las mujeres (0,94 y 0,68 kg/m2).Abstract Introduction: the main objectives of weight-loss interventions are to decrease fat mass while maintaining fatfree mass. Objective: our aim was to address effectiveness body composition changes in overweight adolescents assessed by different body composition methods following an obesity intervention programme. Material and methods: the life-style intervention was multi-disciplinary, with 13 months follow-up. Participants were 13-to-16 year-old overweight, or obese, Spanish adolescents. The adolescents (n = 156; 54.8% females) had body composition measured with anthropometry, dual-energy X-ray absorptiometry and air-displacement plethysmography. All measurements were made at baseline, and after 2- and 13-months. Repeated measures analysis of covariance to compare mean anthropometric changes over time and the Bonferroni correction were applied. Imputation of anthropometric measures was performed. Results: a high significant decrease in fat mass index was achieved in males after 2-and 13-months of intervention as measured by anthropometry (1.16 and 1.56 kg / m2, respectively), X-ray absorptiometry (1.51 and 1.91 kg / m2) and plethysmography (2.13 and 2.44 kg/m2). Moreover, a short and long-term maintenance of fat-and fat-free mass index was observed by X-ray absorptiometry in females (0.94 and 0.68 kg/m2)

Non-productive angiogenesis disassembles Aß plaque-associated blood vessels

The human Alzheimer’s disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD

Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial

[EN]The purpose of this study was to confirm overall survival (OS) and other clinical benefits with bortezomib, melphalan, and prednisone (VMP) versus melphalan and prednisone (MP) in the phase III VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial after prolonged follow-up, and evaluate the impact of subsequent therapies. Previously untreated symptomatic patients with myeloma ineligible for high-dose therapy received up to nine 6-week cycles of VMP (n = 344) or MP (n = 338). With a median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP versus MP (hazard ratio, 0.653; P < .001); median OS was not reached with VMP versus 43 months with MP; 3-year OS rates were 68.5% versus 54.0%. Response rates to subsequent thalidomide- (41% v 53%) and lenalidomide-based therapies (59% v 52%) appeared similar after VMP or MP; response rates to subsequent bortezomib-based therapy were 47% versus 59%. Among patients treated with VMP (n = 178) and MP (n = 233), median survival from start of subsequent therapy was 30.2 and 21.9 months, respectively, and there was no difference in survival from salvage among patients who received subsequent bortezomib, thalidomide, or lenalidomide. Rates of adverse events were higher with VMP versus MP during cycles 1 to 4, but similar during cycles 5 to 9. With VMP, 79% of peripheral neuropathy events improved within a median of 1.9 months; 60% completely resolved within a median of 5.7 months. VMP significantly prolongs OS versus MP after lengthy follow-up and extensive subsequent antimyeloma therapy. First-line bortezomib use does not induce more resistant relapse. VMP used upfront appears more beneficial than first treating with conventional agents and saving bortezomib- and other novel agent-based treatment until relapse