Glycine is able to induce both a motility speed in- and decrease during zebrafish neuronal migration

Various neurotransmitters influence neuronal migration in the developing zebrafish hindbrain. Migrating tegmental hindbrain nuclei neurons (THNs) are governed by depolarizing neurotransmitters (acetylcholine and glutamate), and glycine. In mature neurons, glycine binds to its receptor to hyperpolarize cells. This effect depends on the co-expression of the solute carrier KCC2. Immature precursors, however, typically express NKCC1 instead of KCC2, leading to membrane depolarization upon glycine receptor activation. As neuronal migration occurs in neurons after leaving the cell cycle and before terminal differentiation, we hypothesized that the switch from NKCC1 to KCC2 expression could alter the effect of glycine on THN migration. We tested this notion using in vivo cell tracking, overexpression of glycine receptor mutations and whole mount in situ hybridization. We summarize our findings in a speculative model, combining developmental age, glycine receptor strength and solute carrier expression to describe the effect of glycine on the migration of THNs

Quasilocal equilibrium condition for black ring

We use the conservation of the renormalized boundary stress-energy tensor to obtain the equilibrium condition for a general (thin or fat) black ring solution. We also investigate the role of the spatial stress in the thermodynamics of deformation within the quasilocal formalism of Brown and York and discuss the relation with other methods. In particular, we discuss the quantum statistical relation for the unbalanced black ring solution.Comment: v2: refs. added, matches the published versio

Predictions of mb/mτm_b/m_{\tau} and mtm_t in an Asymptotically Non-Free Theory

We discuss an extention of the Minimal Supersymmetric Standard Model (MSSM) with the 4th and anti-4th generations which have $SU(2)_L\times U(1)_Y$ invariant masses. Due to the the extra generations, all three running gauge couplings become asymptotically non--free while preserving gauge coupling unification at the GUT scale. We show that due to the asymptotically non--free character of the gauge couplings: (1) the top and bottom Yukawa couplings are strongly focused onto infrared fixed points as they are evolved down in scale making their values at \mu=\mz insensitive to their initial values at \mu=\mgut; (2) the model predicts \R(\mz) \equiv Y_b/Y_\tau |_{\mu =\mz}\approx 1.8, which is consistent with the experimental value provided we take the ratio of Yukawa couplings at the GUT scale to be \R(\mgut) = Y_b/Y_\tau |_{\mu = \mgut} = 1/3; (3) the $t$ mass prediction comes out to be \mt\approx 180\,\GeV which is also consistent with experiment.Comment: 20 pgs. 7 figures. Latex2e. othersym.sty, suceqn.sty include

Serious Adverse Drug Reactions in Children and Adolescents Treated On- and Off-Label with Antidepressants and Antipsychotics in Clinical Practice

Introduction: Despite the growing evidence base for psychotropic drug treatment in pediatric patients, knowledge about the benefit-risk ratio in clinical practice remains limited. The 'Therapeutic Drug Monitoring (TDM)-VIGIL' study aimed to evaluate serious adverse drug reactions (ADRs) in children and adolescents treated with antidepressants and/or antipsychotics in approved ('on-label'), and off-label use in clinical practice. Methods: Psychiatric pediatric patients aged 6-18 years treated with antidepressants and/or antipsychotics either on-label or off-label were prospectively followed between October 2014 and December 2018 within a multicenter trial. Follow-up included standardized assessments of response, serious ADRs and therapeutic drug monitoring. Results: 710 youth (age=14.6±2.2 years, female=66.6%) were observed for 5.5 months on average; 76.3% received antidepressants, 47.5% antipsychotics, and 25.2% both. Altogether, 55.2% of the treatment episodes with antidepressants and 80.7% with antipsychotics were off-label. Serious ADRs occurred in 8.3% (95%CI=6.4-10.6%) of patients, mainly being psychiatric adverse reactions (77.4%), predominantly suicidal ideation and behavior. The risk of serious ADRs was not significantly different between patients using psychotropics off-label and on-label (antidepressants: 8.1% vs. 11.3%, p=0.16; antipsychotics: 8.7% vs 7.5%, p=0.67). Serious ADRs occurred in 16.6% of patients who were suicidal at enrollment versus 5.6% of patients who were not suicidal (relative risk 3.0, 95%CI=1.9-4.9). Conclusion: Off-label use of antidepressants and antipsychotics in youth was not a risk factor for the occurrence of serious ADRs in a closely monitored clinical setting. Results from large naturalistic trials like ours can contribute to bridging the gap between knowledge from randomized controlled trials and real-world clinical settings

Observation of hard scattering in photoproduction events with a large rapidity gap at HERA

Events with a large rapidity gap and total transverse energy greater than 5 GeV have been observed in quasi-real photoproduction at HERA with the ZEUS detector. The distribution of these events as a function of the $\gamma p$ centre of mass energy is consistent with diffractive scattering. For total transverse energies above 12 GeV, the hadronic final states show predominantly a two-jet structure with each jet having a transverse energy greater than 4 GeV. For the two-jet events, little energy flow is found outside the jets. This observation is consistent with the hard scattering of a quasi-real photon with a colourless object in the proton.Comment: 19 pages, latex, 4 figures appended as uuencoded fil

Therapeutic drug monitoring of sertraline in children and adolescents: A naturalistic study with insights into the clinical response and treatment of obsessive-compulsive disorder.

BACKGROUND Sertraline is a selective serotonin reuptake inhibitor with specific indications in child and adolescent psychiatry. Notwithstanding its frequent use and clinical benefits, the relationship between pharmacokinetics, pharmacodynamics, efficacy, and tolerability of sertraline across indications, particularly in non-adult patients, is not fully understood. METHOD This naturalistic therapeutic drug monitoring (TDM) study was conducted in a transdiagnostic sample of children and adolescents treated with sertraline (n = 78; mean age, 14.22 ± 2.39; range, 7-18 years) within the prospective multicenter "TDM-VIGIL" project. Associations between dose, serum concentration, and medication-specific therapeutic and side effects based on the Clinical Global Impression scale were examined. Tolerability was measured qualitatively with the 56-item Pediatric Adverse Event Rating Scale. RESULTS A strong linear positive dose-serum concentration relationship (with dose explaining 45% of the variance in concentration) and significant effects of weight and co-medication were found. Neither dose nor serum concentration were associated with side effects. An overall mild-to-moderate tolerability profile of sertraline was observed. In contrast with the transdiagnostic analysis that did not indicate an effect of concentration, when split into depression (MDD) and obsessive-compulsive disorder (OCD) diagnoses, the probability of clinical improvement significantly increased as both dose and concentration increased for OCD, but not for MDD. CONCLUSIONS This TDM-flexible-dose study revealed a significant diagnosis-specific effect between sertraline serum concentration and clinical efficacy for pediatric OCD. While TDM already guides clinical decision-making regarding compliance, dose calibration, and drug-drug interactions, combining TDM with other methods, such as pharmacogenetics, may facilitate a personalized medicine approach in psychiatry

Electrospun PLLA Nanofiber Scaffolds and Their Use in Combination with BMP-2 for Reconstruction of Bone Defects

Introduction Adequate migration and differentiation of mesenchymal stem cells is essential for regeneration of large bone defects. To achieve this, modern graft materials are becoming increasingly important. Among them, electrospun nanofiber scaffolds are a promising approach, because of their high physical porosity and potential to mimic the extracellular matrix (ECM). Materials and Methods The objective of the present study was to examine the impact of electrospun PLLA nanofiber scaffolds on bone formation in vivo, using a critical size rat calvarial defect model. In addition we analyzed whether direct incorporation of bone morphogenetic protein 2 (BMP-2) into nanofibers could enhance the osteoinductivity of the scaffolds. Two critical size calvarial defects (5 mm) were created in the parietal bones of adult male Sprague-Dawley rats. Defects were either (1) left unfilled, or treated with (2) bovine spongiosa, (3) PLLA scaffolds alone or (4) PLLA/BMP-2 scaffolds. Cranial CT-scans were taken at fixed intervals in vivo. Specimens obtained after euthanasia were processed for histology, histomorphometry and immunostaining (Osteocalcin, BMP-2 and Smad5). Results PLLA scaffolds were well colonized with cells after implantation, but only showed marginal ossification. PLLA/BMP-2 scaffolds showed much better bone regeneration and several ossification foci were observed throughout the defect. PLLA/BMP-2 scaffolds also stimulated significantly faster bone regeneration during the first eight weeks compared to bovine spongiosa. However, no significant differences between these two scaffolds could be observed after twelve weeks. Expression of osteogenic marker proteins in PLLA/BMP-2 scaffolds continuously increased throughout the observation period. After twelve weeks osteocalcin, BMP-2 and Smad5 were all significantly higher in the PLLA/BMP-2 group than in all other groups. Conclusion Electrospun PLLA nanofibers facilitate colonization of bone defects, while their use in combination with BMP-2 also increases bone regeneration in vivo and thus combines osteoconductivity of the scaffold with the ability to maintain an adequate osteogenic stimulus

Functionalisation of PLLA nanofiber scaffolds using a possible cooperative effect between collagen type I and BMP-2: impact on growth and osteogenic differentiation of human mesenchymal stem cells

Mesenchymal stem cell differentiation of osteoblasts is triggered by a series of signaling processes including integrin and bone morphogenetic protein (BMP), which therefore act in a cooperative manner. The aim of this study was to analyze whether these processes can be remodeled in an artificial poly-(l)-lactide acid (PLLA) based nanofiber scaffold. Matrices composed of PLLA-collagen type I or BMP-2 incorporated PLLA-collagen type I were seeded with human mesenchymal stem cells (hMSC) and cultivated over a period of 22 days, either under growth or osteoinductive conditions. During the course of culture, gene expression of alkaline phosphatase (ALP), osteocalcin (OC) and collagen I (COL-I) as well as Smad5 and focal adhesion kinase (FAK), two signal transduction molecules involved in BMP-2 or integrin signaling were analyzed. Furthermore, calcium and collagen I deposition, as well as cell densities and proliferation, were determined using fluorescence microscopy. The incorporation of BMP-2 into PLLA-collagen type I nanofibers resulted in a decrease in diameter as well as pore sizes of the scaffold. Mesenchymal stem cells showed better adherence and a reduced proliferation on BMP-containing scaffolds. This was accompanied by an increase in gene expression of ALP, OC and COL-I. Furthermore the presence of BMP-2 resulted in an upregulation of FAK, while collagen had an impact on the gene expression of Smad5. Therefore these different strategies can be combined in order to enhance the osteoblast differentiation of hMSC on PLLA based nanofiber scaffold. By doing this, different signal transduction pathways seem to be up regulated

Physicians' attitudes about obesity and their associations with competency and specialty: A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Physicians frequently report negative attitudes about obesity which is thought to affect patient care. However, little is known about how attitudes toward treating obese patients are formed. We conducted a cross-sectional survey of physicians in order to better characterize their attitudes and explore the relationships among attitudes, perceived competency in obesity care, including report of weight loss in patients, and other key physician, training, and practice characteristics.</p> <p>Methods</p> <p>We surveyed all 399 physicians from internal medicine, pediatrics, and psychiatry specialties at one institution regarding obesity care attitudes, competency, including physician report of percent of their patients who lose weight. We performed a factor analysis on the attitude items and used hierarchical regression analysis to explore the degree to which competency, reported weight loss, physician, training and practice characteristics explained the variance in each attitude factor.</p> <p>Results</p> <p>The overall response rate was 63%. More than 40% of physicians had a negative reaction towards obese patients, 56% felt qualified to treat obesity, and 46% felt successful in this realm. The factor analysis revealed 4 factors–<it>Physician Discomfort/Bias, Physician Success/Self Efficacy, Positive Outcome Expectancy</it>, and <it>Negative Outcome Expectancy</it>. Competency and reported percent of patients who lose weight were most strongly associated with the <it>Physician Success/Self Efficacy </it>attitude factor. Greater skill in patient assessment was associated with less <it>Physician Discomfort/Bias</it>. Training characteristics were associated with outcome expectancies with newer physicians reporting more positive treatment expectancies. Pediatric faculty was more positive and psychiatry faculty less negative in their treatment expectancies than internal medicine faculty.</p> <p>Conclusion</p> <p>Physician attitudes towards obesity are associated with competency, specialty, and years since postgraduate training. Further study is necessary to determine the direction of influence and to explore the impact of these attitudes on patient care.</p