Mechanical Properties and Biological Responses of Bioactive Glass Ceramics Processed using Indirect SLS

This paper will report on research which aims to generate bone replacement components by processing bioactive glass-ceramic powders using indirect selective laser sintering. The indirect SLS route has been chosen as it offers the ability to tailor the shape of the implant to the implantation site, and two bioactive glass ceramic materials have been processed through this route: apatite-mullite and apatite-wollostanite. The results of bend tests, to investigate mechanical properties, and in vitro and in vivo experiments to investigate biological responses of the materials will be reported, and the suitability of completed components for implant will be assessed.Mechanical Engineerin

Nomenclature and heterogeneity : consequences for the use of mesenchymal stem cells in regenerative medicine

Mesenchymal stem cells (MSCs) are in development for many clinical indications, based both on “stem” properties (tissue repair or regeneration) and on signalling repertoire (immunomodulatory and anti-inflammatory effects). Potential conflation of MSC properties with those of tissue-derived stromal cells presents difficulties in comparing study outcomes and represents a source of confusion in cell therapy development. Cultured MSCs demonstrate significant heterogeneity in clonogenicity and multi-lineage differentiation potential. However in vivo biology of MSCs includes native functions unrelated to regenerative medicine applications, so do nomenclature and heterogeneity matter? In this perspective we examine some consequences of the nomenclature debate and heterogeneity of MSCs. Regulatory expectations are considered, emphasising that product development should prioritise detailed characterisation of therapeutic cell populations for specific indications

Dopaminergic drugs and the risk of hip or femur fracture: a population-based case–control study

SUMMARY: The effect of dopaminergic medication on the risk of hip/femur fractures is not clear. Our results showed a nearly twofold increased risk of hip/femur fractures in current dopaminergic drug users. Concomitant use of antidepressants further increased this risk. Fracture risk assessment may be warranted in elderly users of dopaminergic drugs. INTRODUCTION: Dopaminergic drugs, often used in the treatment of Parkinson's disease, have several pharmacological effects that may increase or decrease the risk of falling and fractures. Thus, the effect of dopaminergic medication on the risk of hip/femur fractures is not clear. The objective of the study was to examine the effect of dopaminergic medication and concomitant use of psychotropics on the risk of hip/femur fractures taking into account the timing of dopaminergic drug use. METHODS: A population-based case-control study in the PHARMO database was conducted for the period 1991 to 2002. Cases were patients aged 18 years and older with a first hip or femur fracture and matched to four control patients by year of birth, sex and geographical region. RESULTS: The study population included 6,763 cases and 26,341 controls. Current use of dopaminergic drugs (1-30 days before the index date) was associated with an increased risk of hip/femur fractures compared to never use (OR(adj) 1.76, 95% CI = 1.39-2.22), but this excess risk rapidly dropped to baseline levels when treatment had been discontinued >1 year ago. Concomitant use of antidepressants among current dopaminergic drug users further increased the risk of hip/femur fractures (OR(adj) 3.51, 95% CI = 2.10-5.87) while there was no additional risk with concomitant use of other psychotropics. CONCLUSIONS: Although the observed association between dopaminergic drugs and fracture risk may not be entirely causal, due to absence of information on the (severity of the) underlying disease, fracture risk assessment may be warranted in elderly users of dopaminergic drugs

Upregulation of P2Y2 receptors by retinoids in normal human epidermal keratinocytes

Retinoids, vitamin A derivatives, are important regulators of the growth and differentiation of skin cells. Although retinoids are therapeutically used for several skin ailments, little is known about their effects on P2 receptors, known to be involved in various functions in the skin. DNA array analysis showed that treatment of normal human epidermal keratinocytes (NHEKs) with all-trans-retinoic acid (ATRA), an agonist to RAR (retinoic acid receptor), enhanced the expression of mRNA for the P2Y2 receptor, a metabotropic P2 receptor that is known to be involved in the proliferation of the epidermis. The expression of other P2 receptors in NHEKs was not affected by ATRA. ATRA increased the mRNA for the P2Y2 receptor in a concentration-dependent fashion (1 nM to 1 μM). Am80, a synthesized agonist to RAR, showed a similar enhancement, whereas 9-cis-retinoic acid (9-cisRA), an agonist to RXR (retinoid X receptor), enhanced P2Y2 gene expression to a lesser extent. Ca2+ imaging analysis showed that ATRA also increased the function of P2Y2 receptors in NHEKs. Retinoids are known to enhance the turnover of the epidermis by increasing both proliferation and terminal differentiation. The DNA microarray analysis also revealed that ATRA upregulates various genes involved in the differentiation of NHEKs. Our present results suggest that retinoids, at least in part, exert their proliferative effects by upregulating P2Y2 receptors in NHEKs. This effect of retinoids may be closely related to their therapeutic effect against various ailments or aging events in skins such as over-keratinization, pigmentation and re-modeling

Ketamine Influences CLOCK:BMAL1 Function Leading to Altered Circadian Gene Expression

Major mood disorders have been linked to abnormalities in circadian rhythms, leading to disturbances in sleep, mood, temperature, and hormonal levels. We provide evidence that ketamine, a drug with rapid antidepressant effects, influences the function of the circadian molecular machinery. Ketamine modulates CLOCK:BMAL1-mediated transcriptional activation when these regulators are ectopically expressed in NG108-15 neuronal cells. Inhibition occurs in a dose-dependent manner and is attenuated after treatment with the GSK3β antagonist SB21673. We analyzed the effect of ketamine on circadian gene expression and observed a dose-dependent reduction in the amplitude of circadian transcription of the Bmal1, Per2, and Cry1 genes. Finally, chromatin-immunoprecipitation analyses revealed that ketamine altered the recruitment of the CLOCK:BMAL1 complex on circadian promoters in a time-dependent manner. Our results reveal a yet unsuspected molecular mode of action of ketamine and thereby may suggest possible pharmacological antidepressant strategies

Non-epithelial oral mucosal progenitor cell populations

This review considers the potential existence and role of stem or progenitor cell populations within the non-epithelial tissues of the oral mucosa. Currently, there is little published evidence supporting this hypothesis; however, because of the similarities in structure and function of the oral mucosa and skin, findings within the dermis of the skin may potentially reflect the situation within the oral mucosa. Over recent years, the identification of the skin as a local reservoir of adult stem cell populations and the idea that multipotent cell populations exist within the dermal tissues of skin has gained increasing credibility. Indeed, numerous multipotent progenitor cells have been identified within the dermis and resident appendages, all capable of differentiating into multiple cell lineages. Furthermore, a number of these cell populations have been implicated in the repair of these tissues following injury. There is increasing evidence suggesting that such populations of progenitor cells may also reside within the lamina propria. In this respect, the ability to isolate large numbers of multipotent progenitor cells from a tissue which when biopsied heals without a scar would be of great interest scientifically and commercially, particularly with respect to future therapeutic applications and the developing discipline of tissue engineering