Bone regenerative potential of the selective sphingosine 1-phosphate receptor modulator siponimod: In vitro characterisation using osteoblast and endothelial cells

The repair of critical bone defects remains a significant therapeutic challenge. While the implantation of drug-eluting scaffolds is an option, a drug with the optimal pharmacological properties has not yet been identified. Agents acting at sphingosine 1-phosphate (S1P) receptors have been considered, but those investigated so far do not discriminate between the five known S1P receptors. This work was undertaken to investigate the potential of the specific S1P1/5 modulator siponimod as a bone regenerative agent, by testing in vitro its effect on cell types critical to the bone regeneration process. hFOB osteoblasts and HUVEC endothelial cells were treated with siponimod and other S1P receptor modulators and investigated for changes in intracellular cyclic AMP content, viability, proliferation, differentiation, attachment and cellular motility. Siponimod showed no effect on the viability and proliferation of osteoblasts and endothelial cells, but increased osteoblast differentiation (as shown by increased alkaline phosphatase activity). Furthermore, siponimod significantly increased endothelial cell motility in scratch and transwell migration assays. These effects on osteoblast differentiation and endothelial cell migration suggest that siponimod may be a potential agent for the stimulation of localised differentiation of osteoblasts in critical bone defects

Natural emotion vocabularies and borderline personality disorder

Background Emotion dysregulation is a characteristic central to borderline personality disorder (BPD). Valuably, verbal behaviour can provide a unique perspective for studying emotion dysregulation in BPD, with recent research suggesting that the varieties of emotion words one actively uses (i.e., active emotion vocabularies [EVs]) reflect habitual experience and potential dysregulation therein. Accordingly, the present research examined associations between BPD and active EVs across two studies. Methods Study 1 (N = 530) comprised a large non-clinical sample recruited from online forums, whereby BPD traits were measured via self-report. Study 2 (N = 64 couples) consisted of mixed-gender romantic couples in which the woman had a BPD diagnosis, as well as a control group of couples. In both studies, participants’ verbal behaviours were analysed to calculate their active EVs. Results Results from both studies revealed BPD to be associated with larger negative EV (i.e., using a broad variation of unique negative emotion words), which remained robust when controlling for general vocabulary size and negative affect word frequency in Study 2. The association between BPD and negative EV was insensitive to context. Limitations Limitations of this research include: 1) the absence of a clinical control group; 2) typical constraints surrounding word-counting approaches; and 3) the cross-sectional design (causality cannot be inferred). Conclusions Our findings contribute to BPD theory as well as the broader language and emotion literature. Importantly, these findings provide new insight into how individuals manifesting BPD attend to and represent their emotional experiences, which could be used to inform clinical practice

Sphingosine 1-phosphate, a potential target in neovascular retinal disease

Neovascular ocular diseases (such as age-related macular degeneration, diabetic retinopathy and retinal vein occlusion) are characterised by common pathological processes that contribute to disease progression. These include angiogenesis, oedema, inflammation, cell death and fibrosis. Currently available therapies target the effects of vascular endothelial growth factor (VEGF), the main mediator of pathological angiogenesis. Unfortunately, VEGF blockers are expensive biological therapeutics that necessitate frequent intravitreal administration and are associated with multiple adverse effects. Thus, alternative treatment options associated with fewer side effects are required for disease management. This review introduces sphingosine 1-phosphate (S1P) as a potential pharmacological target for the treatment of neovascular ocular pathologies. S1P is a sphingolipid mediator that controls cellular growth, differentiation, survival and death. S1P actions are mediated by five G protein-coupled receptors (S1P1-5 receptors) which are abundantly expressed in all retinal and subretinal structures. The action of S1P on S1P1 receptors can reduce angiogenesis, increase endothelium integrity, reduce photoreceptor apoptosis and protect the retina against neurodegeneration. Conversely, S1P2 receptor signalling can increase neovascularisation, disrupt endothelial junctions, stimulate VEGF release, and induce retinal cell apoptosis and degeneration of neural retina. The aim of this review is to thoroughly discuss the role of S1P and its different receptor subtypes in angiogenesis, inflammation, apoptosis and fibrosis in order to determine which of these S1P-mediated processes may be targeted therapeutically

Sphingosine 1-phosphate (S1P) signalling: role in bone biology and potential therapeutic target for bone repair

The lipid mediator sphingosine 1-phosphate (S1P) affects cellular functions in most systems. Interest in its therapeutic potential has increased following the discovery of its G protein-coupled receptors and the recent availability of agents that can be safely administered in humans. Although the role of S1P in bone biology has been the focus of much less research than its role in the nervous, cardiovascular and immune systems, it is becoming clear that this lipid influences many of the functions, pathways and cell types that play a key role in bone maintenance and repair. Indeed, S1P is implicated in many osteogenesis-related processes including stem cell recruitment and subsequent differentiation, differentiation and survival of osteoblasts, and coupling of the latter cell type with osteoclasts. In addition, S1P’s role in promoting angiogenesis is well-established. The pleiotropic effects of S1P on bone and blood vessels have significant potential therapeutic implications, as current therapeutic approaches for critical bone defects show significant limitations. Because of the complex effects of S1P on bone, the pharmacology of S1P-like agents and their physico-chemical properties, it is likely that therapeutic delivery of S1P agents will offer significant advantages compared to larger molecular weight factors. Hence, it is important to explore novel methods of utilizing S1P agents therapeutically, and improve our understanding of how S1P and its receptors modulate bone physiology and repair

Fully automated convolutional neural network-based affine algorithm improves liver registration and lesion co-localization on hepatobiliary phase T1-weighted MR images.

BackgroundLiver alignment between series/exams is challenged by dynamic morphology or variability in patient positioning or motion. Image registration can improve image interpretation and lesion co-localization. We assessed the performance of a convolutional neural network algorithm to register cross-sectional liver imaging series and compared its performance to manual image registration.MethodsThree hundred fourteen patients, including internal and external datasets, who underwent gadoxetate disodium-enhanced magnetic resonance imaging for clinical care from 2011 to 2018, were retrospectively selected. Automated registration was applied to all 2,663 within-patient series pairs derived from these datasets. Additionally, 100 within-patient series pairs from the internal dataset were independently manually registered by expert readers. Liver overlap, image correlation, and intra-observation distances for manual versus automated registrations were compared using paired t tests. Influence of patient demographics, imaging characteristics, and liver uptake function was evaluated using univariate and multivariate mixed models.ResultsCompared to the manual, automated registration produced significantly lower intra-observation distance (p < 0.001) and higher liver overlap and image correlation (p < 0.001). Intra-exam automated registration achieved 0.88 mean liver overlap and 0.44 mean image correlation for the internal dataset and 0.91 and 0.41, respectively, for the external dataset. For inter-exam registration, mean overlap was 0.81 and image correlation 0.41. Older age, female sex, greater inter-series time interval, differing uptake, and greater voxel size differences independently reduced automated registration performance (p ≤ 0.020).ConclusionA fully automated algorithm accurately registered the liver within and between examinations, yielding better liver and focal observation co-localization compared to manual registration

A Modified Surface on Titanium Deposited by a Blasting Process

Abstract : Hydroxyapatite (HA) coating of hard tissue implants is widely employed for its biocompatible and osteoconductive properties as well as its improved mechanical properties. Plasma technology is the principal deposition process for coating HA on bioactive metals for this application. However, thermal decomposition of HA can occur during the plasma deposition process, resulting in coating variability in terms of purity, uniformity and crystallinity, which can lead to implant failure caused by aseptic loosening. In this study, CoBlast™, a novel blasting process has been used to successfully modify a titanium (V) substrate with a HA treatment using a dopant/abrasive regime. The impact of a series of apatitic abrasives under the trade name MCD, was investigated to determine the effect of abrasive particle size on the surface properties of both microblast (abrasive only) and CoBlast (HA/abrasive) treatments. The resultant HA treated substrates were compared to substrates treated with abrasive only (microblasted) and an untreated Ti. The HA powder, apatitic abrasives and the treated substrates were characterized for chemical composition, coating coverage, crystallinity and topography including surface roughness. The results show that the surface roughness of the HA blasted modification was affected by the particle size of the apatitic abrasives used. The CoBlast process did not alter the chemistry of the crystalline HA during deposition. Cell proliferation on the HA surface was also assessed, which demonstrated enhanced osteo-viability compared to the microblast and blank Ti. This study demonstrates the ability of the CoBlast process to deposit HA coatings with a range of surface properties onto Ti substrates. The ability of the CoBlast technology to offer diversity in modifying surface topography offers exciting new prospects in tailoring the properties of medical devices for applications ranging from dental to orthopedic settings

In vitro dissolution models for the prediction of in vivo performance of an oral mesoporous silica formulation

Drug release from mesoporous silica systems has been widely investigated in vitro using USP Type II (paddle) dissolution apparatus. However, it is not clear if the observed enhanced in vitro dissolution can forecast drug bioavailability in vivo. In this study, the ability of different in vitro dissolution models to predict in vivo oral bioavailability in a pig model was examined. The fenofibrate-loaded mesoporous silica formulation was compared directly to a commercial reference product, Lipantil Supra®. Three in vitro dissolution methods were considered; USP Type II (paddle) apparatus, USP Type IV (flow-through cell) apparatus and a USP IV Transfer model (incorporating a SGF to FaSSIF-V2 media transfer). In silico modelling, using a physiologically based pharmacokinetic modelling and simulation software package (Gastroplus™), to generate in vitro/in vivo relationships was also investigated. The study demonstrates that the in vitro dissolution performance of a mesoporous silica formulation varies depending on the dissolution apparatus utilised and experimental design. The findings show that the USP IV transfer model was the best predictor of in vivo bioavailability. The USP Type II (paddle) apparatus was not effective at forecasting in vivo behaviour. This observation is likely due to hydrodynamic differences between the two apparatus and the ability of the transfer model to better simulate gastrointestinal transit. The transfer model is advantageous in forecasting in vivo behaviour for formulations which promote drug supersaturation and as a result are prone to precipitation to a more energetically favourable, less soluble form. The USP IV transfer model could prove useful in future mesoporous silica formulation development. In silico modelling has the potential to assist in this process. However, further investigation is required to overcome the limitations of the model for solubility enhancing formulations

Magnetic core-shell nanoparticles for drug delivery by nebulization

BACKGROUND: Aerosolized therapeutics hold great potential for effective treatment of various diseases including lung cancer. In this context, there is an urgent need to develop novel nanocarriers suitable for drug delivery by nebulization. To address this need, we synthesized and characterized a biocompatible drug delivery vehicle following surface coating of Fe(3)O(4) magnetic nanoparticles (MNPs) with a polymer poly(lactic-co-glycolic acid) (PLGA). The polymeric shell of these engineered nanoparticles was loaded with a potential anti-cancer drug quercetin and their suitability for targeting lung cancer cells via nebulization was evaluated. RESULTS: Average particle size of the developed MNPs and PLGA-MNPs as measured by electron microscopy was 9.6 and 53.2 nm, whereas their hydrodynamic swelling as determined using dynamic light scattering was 54.3 nm and 293.4 nm respectively. Utilizing a series of standardized biological tests incorporating a cell-based automated image acquisition and analysis procedure in combination with real-time impedance sensing, we confirmed that the developed MNP-based nanocarrier system was biocompatible, as no cytotoxicity was observed when up to 100 μg/ml PLGA-MNP was applied to the cultured human lung epithelial cells. Moreover, the PLGA-MNP preparation was well-tolerated in vivo in mice when applied intranasally as measured by glutathione and IL-6 secretion assays after 1, 4, or 7 days post-treatment. To imitate aerosol formation for drug delivery to the lungs, we applied quercitin loaded PLGA-MNPs to the human lung carcinoma cell line A549 following a single round of nebulization. The drug-loaded PLGA-MNPs significantly reduced the number of viable A549 cells, which was comparable when applied either by nebulization or by direct pipetting. CONCLUSION: We have developed a magnetic core-shell nanoparticle-based nanocarrier system and evaluated the feasibility of its drug delivery capability via aerosol administration. This study has implications for targeted delivery of therapeutics and poorly soluble medicinal compounds via inhalation route

Evaluating the impact of a community health worker program on non-communicable disease, malnutrition, tuberculosis, family planning and antenatal care in Neno, Malawi : protocol for a stepped-wedge, cluster randomized controlled trial

Introduction: This protocol concerns the implementation and evaluation of an intervention designed to realign the existing cadre of Community Health Workers (CHWs) in Neno District, Malawi to better support the care needs of the clients they serve. The proposed intervention is a ‘Household Model’ where CHWs will be reassigned to households, rather than to specific patients with HIV and/or TB. Methods and Analysis: Using a stepped-wedge, cluster-randomized design, this study investigates whether high HIV retention rates can be replicated for non-communicable diseases (NCDs), and the Model’s impact on TB and pediatric malnutrition case-finding, as well as the uptake of family planning and antenatal care. Eleven sites (health centres and hospitals) were arranged into six clusters (average cluster population 21,800). Primary outcomes include retention in care for HIV and chronic NCDs, TB case finding, pediatric malnutrition case finding, and utilization of early and complete antenatal. Clinical outcomes are based on routinely collected data the Ministry of Health’s District Health Information System 2 and an OpenMRS Electronic Medical Record supported by Partners In Health. Additionally, semi-structured qualitative interviews with various stakeholders will assess community perceptions and context of the Household Model. Ethics and dissemination: Ethics approval has been obtained from the Malawian National Health Science Research Committee (#16/11/1694) in Lilongwe, Malawi; Partners Healthcare Human Research Committee (#2017P000548/PHS) in Somerville, Massachusetts; and by the Biomedical and Scientific Research Ethics Sub-Committee (REGO-2017-2060) at the University of Warwick in Coventry, United Kingdom. Dissemination will include manuscripts for peer-reviewed publication as well as a full report detailing the findings of the intervention for the Malawian Ministry of Health. Registration: Registered on ClinicalTrials.gov in April 2017. Identifier: NCT0310672

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