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Charopoulos I.,University of Leeds | Orme S.,Leeds General Infirmary | Giannoudis P.V.,University of Leeds | Giannoudis P.V.,Academic Unit
Expert Opinion on Drug Safety

Introduction: Bone strength determinants such as bone mineral density and bone quality parameters are determined by life-long remodeling of skeletal tissue. Denosumab is a fully human mAb receptor activator of NF-κB ligand, which selectively inhibits osteoclastogenesis, the end product of a cascade interaction among numerous systemic and local factors and osteoblasts. It has been approved for clinical use by the FDA in the US and by the European Medicines Agency in Europe since June 2010 (trade name Prolia™, Amgen, Thousand Oaks, CA, USA). Areas covered: This review establishes the concerns and provides insights in issues concerning the cost-effectiveness and safety profile of this new pharmaceutical agent. There is an effort to clarify the special characteristics and the anti-catabolic role of denosumab in the bone tissue homeostasis and more specifically its potential clinical applications and clinical results in the field of postmenopausal osteoporosis. Expert opinion: Administrated as a subcutaneous injection every 6 months, denosumab has been shown to decrease bone turnover and increase bone mineral density in postmenopausal women with low bone mass or osteoporosis and reduce vertebral, hip and nonvertebral fracture risk in postmenopausal women with osteoporosis. The rapid, sustained and reversible effect in suppressing osteoclastic bone resorption, the return of responsiveness on rechallenge, its good tolerability and ease of administration are features that distinguish it from other antiresorptive therapies. © 2011 Informa UK, Ltd. Source

Cuthbert R.J.,University of Leeds | Cuthbert R.J.,Leeds Institute of Molecular Medicine | Churchman S.M.,University of Leeds | Churchman S.M.,Leeds Institute of Molecular Medicine | And 8 more authors.

Objective: Surgically induced periosteal membrane holds great potential for the treatment of large bone defects representing a simple alternative to combinations of exogenous stem cells, scaffolds and growth factors. The purpose of this study was to explore the biological basis for this novel regenerative medicine strategy in man. Methods: Eight patients with critical size defects were treated with the induced membrane (IM) technique. After membrane formation 1cm2 biopsy was taken together with matched, healthy diaphyseal periosteum (P) for comparative analysis. Morphological characteristics, cell composition and growth factor expression were compared. Functional and molecular evaluation of mesenchymal stromal cell (MSC) activity was performed. Results: Both tissues shared similar morphology although IM was significantly thicker than P (p=0.032). The frequency of lymphocytes, pericytes (CD45-CD34-CD146+) and cells expressing markers consistent with bone marrow MSCs (CD45-/lowCD271bright) were 31. 3 and 15.5-fold higher respectively in IM (all p=0.043). IM contained 3-fold more cells per gramme of tissue with a similar proportion of endothelial cells (CD45-CD31+). Expressed bone morphogenic protein 2, vascular endothelial growth factor and stromal derived factor 1 (SDF-1) are key tissue regeneration mediators. Adherent expanded cells from both tissues had molecular profiles similar to bone marrow MSCs but cells from IM expressed greater than 2 fold relative abundance of SDF-1transcript compared to P (p=0.043). Conclusion: The IM is a thick, vascularised structure that resembles periosteum with a cellular composition and molecular profile facilitating large defect repair and therefore may be described as an "induced-periosteum". This tissue offers a powerful example of in situ tissue engineering. © 2013 Elsevier Inc. Source

Ceccherini-Nelli A.,Academic Unit | Priebe S.,Queen Mary, University of London
Social Psychiatry and Psychiatric Epidemiology

Objective Suicides account for more than 30,000 deaths per year in the US alone. Suicide rates change over time, and the factors influencing them remain poorly understood. Economic factors, in particular unemployment, have been suggested as a major influence. However, the evidence for this has been inconsistent, which may be partly explained by shortcomings of the statistical methods used. Methods Time series analytical techniques (unit root and co-integration tests) were applied to test the associations over time between economic factors, i.e. unemployment, real gross domestic product per capita (RGDP) and the consumer price index (CPI) and death rates by suicide as collected by national agencies in the UK (1901-2006), US (1900-1997), France (1970-2004) and Italy (1970-2001). Traditional correlation analyses were used when appropriate. Results Co-integration and correlation tests showed a long-run association between economic factors and suicide rates. Increase/decrease of unemployment predicted an increase/decrease of suicide rates over long historical periods and in different nations. RGDP and the CPI were also linked with suicide rates, but this was not consistently so and the direction of the association varied. Conclusions Unemployment is a major factor influencing suicide rates over long periods of time and in different national contexts. It needs to be considered as a confounding factor in evaluations of suicide prevention strategies. © Springer-Verlag 2010. Source

Hodgetts V.A.,Sandwell and West Birmingham Hospitals NHS Trust | Morris R.K.,University of Birmingham | Morris R.K.,Academic Unit | Francis A.,Perinatal Institute | And 2 more authors.
BJOG: An International Journal of Obstetrics and Gynaecology

Objectives To assess the effect of timing of folic acid (FA) supplementation during pregnancy on the risk of the neonate being small for gestational age (SGA). Design A population database study and a systematic review with meta-analysis including the results of this population study. Setting and data sources A UK regional database was used for the population study and an electronic literature search (from inception until August 2013) for the systematic review. Participants and included studies Singleton live births with no known congenital anomalies; 111 736 in population study and 188 796 in systematic review. Outcome measures, data extraction and analysis The main outcome was SGA based on customised birthweight centile. Associations are presented as odds ratios (OR) and adjusted odds ratios (aOR), adjusted for maternal and pregnancy-related characteristics. Results Of 108 525 pregnancies with information about FA supplementation, 92 133 (84.9%) had taken FA during pregnancy. Time of commencement of supplementation was recorded in 39 416 pregnancies, of which FA was commenced before conception in 10 036, (25.5%) cases. Preconception commencement of FA supplementation was associated with reduced risk of SGA <10th centile (aOR 0.80, 95% CI 0.71-0.90, P < 0.01) and SGA <5th centile (aOR 0.78, 95% CI 0.66-0.91, P < 0.01). This result was reproduced when the data were pooled with other studies in the systematic review, showing a significant reduction in SGA (<5th centile) births with preconception commencement of FA (aOR 0.75, 95% CI 0.61-0.92, P < 0.006). In contrast, postconception folate had no significant effect on SGA rates. Conclusion Supplementation with FA significantly reduces the risk of SGA at birth but only if commenced preconceptually independent of other risk factors. Systematic review registration This systematic review was prospectively registered with PROSPERO number CRD42013004895. © 2014 Royal College of Obstetricians and Gynaecologists. Source

Pountos I.,University of Leeds | Georgouli T.,University of Leeds | Calori G.M.,University of Milan | Giannoudis P.V.,University of Leeds | Giannoudis P.V.,Academic Unit

Nonsteroidal anti-inflammatory drugs (NSAIDs) play an essential part in our approach to control pain in the posttraumatic setting. Over the last decades, several studies suggested that NSAIDs interfere with bone healing while others contradict these findings. Although their analgesic potency is well proven, clinicians remain puzzled over the potential safety issues. We have systematically reviewed the available literature, analyzing and presenting the available in vitro animal and clinical studies on this field. Our comprehensive review reveals the great diversity of the presented data in all groups of studies. Animal and in vitro studies present so conflicting data that even studies with identical parameters have opposing results. Basic science research defining the exact mechanism with which NSAIDs could interfere with bone cells and also the conduction of well-randomized prospective clinical trials are warranted. In the absence of robust clinical or scientific evidence, clinicians should treat NSAIDs as a risk factor for bone healing impairment, and their administration should be avoided in high-risk patients. Copyright 2012 Ippokratis Pountos et al. Source

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