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1.  Epidemiology and Burden of Osteoarthritis 
British medical bulletin  2013;105:185-199.
Background
Osteoarthritis (OA) is a degenerative joint disease involving the cartilage and many of its surrounding tissues. Disease progression is usually slow but can ultimately lead to joint failure with pain and disability. OA of the hips and knees tends to cause the greatest burden to the population as pain and stiffness in these large weight bearing joints often leads to significant disability requiring surgical intervention.
Sources of data
The article reviews the existing data on epidemiology of osteoarthritis and the burden of the disease.
Areas of agreement
Symptoms and radiographic changes are poorly correlated in OA. Established risk factors include obesity, local trauma and occupation. The burden of OA is physical, psychological and socioeconomic.
Areas of controversy
Available data does not allow definite conclusion regarding the roles of nutrition, smoking and sarcopenia as risk factors for developing OA
Growing points
Areas timely for developing research: Further research is required to fully understand how OA affects an individual physically and psychologically, and to determine their healthcare need.
doi:10.1093/bmb/lds038
PMCID: PMC3690438  PMID: 23337796
epidemiology; osteoarthritis; burden
2.  Mitochondrial genetics 
British Medical Bulletin  2013;106(1):135-159.
Introduction
In the last 10 years the field of mitochondrial genetics has widened, shifting the focus from rare sporadic, metabolic disease to the effects of mitochondrial DNA (mtDNA) variation in a growing spectrum of human disease. The aim of this review is to guide the reader through some key concepts regarding mitochondria before introducing both classic and emerging mitochondrial disorders.
Sources of data
In this article, a review of the current mitochondrial genetics literature was conducted using PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). In addition, this review makes use of a growing number of publically available databases including MITOMAP, a human mitochondrial genome database (www.mitomap.org), the Human DNA polymerase Gamma Mutation Database (http://tools.niehs.nih.gov/polg/) and PhyloTree.org (www.phylotree.org), a repository of global mtDNA variation.
Areas of agreement
The disruption in cellular energy, resulting from defects in mtDNA or defects in the nuclear-encoded genes responsible for mitochondrial maintenance, manifests in a growing number of human diseases.
Areas of controversy
The exact mechanisms which govern the inheritance of mtDNA are hotly debated.
Growing points
Although still in the early stages, the development of in vitro genetic manipulation could see an end to the inheritance of the most severe mtDNA disease.
doi:10.1093/bmb/ldt017
PMCID: PMC3675899  PMID: 23704099
mitochondria; genetics; mitochondrial DNA; mitochondrial disease; mtDNA
3.  Neurological disorders and the potential role for stem cells as a therapy 
British Medical Bulletin  2012;101(1):163-181.
Introduction
Neurological disorders are routinely characterized by loss of cells in response to an injury or a progressive insult. Stem cells could therefore be useful to treat these disorders.
Sources of data
Pubmed searches of recent literature.
Areas of agreement
Stem cells exhibit proliferative capacity making them ideally suited for replacing dying cells. However, instead of cell replacement therapy stem cell transplants frequently appear to work via neurotrophic factor release, immunomodulation and upregulation of endogenous stem cells.
Areas of controversy and areas timely for developing research
Many questions remain with respect to the use of stem cells as a therapy, the answers to which will vary depending on the disorder to be treated and mode of action. Whereas the potential tumorigenic capability of stem cells is a concern, most studies do not support this notion. Further determination of the optimal cell type, and whether to perform allogeneic or autologous transplants warrant investigation before the full potential of stem cells can be realized. In addition, the use of stem cells to develop disease models should not be overlooked.
doi:10.1093/bmb/lds001
PMCID: PMC3577100  PMID: 22357552
mesenchymal stem cells; neural stem cells; tumorigenesis; inflammation; neurotrophic factors; cell therapy
4.  Cell-based therapies for lung disease 
British Medical Bulletin  2012;101(1):147-161.
Introduction or background
The adult lung is a complex organ whose large surface area interfaces extensively with both the environment and circulatory system. Yet, in spite of the high potential for exposure to environmental or systemic harm, epithelial cell turnover in adult lung is comparatively slow. Moreover, loss of lung function with advancing age is becoming an increasingly costly healthcare problem. Cell-based therapies stimulating endogenous stem/progenitor cells or supplying exogenous ones have therefore become a prime translational goal. Alternatively when lung repair becomes impossible, replacement with tissue-engineered lung is an attractive emerging alternative using a decellularized matrix or bioengineered scaffold.
Sources of data
Endogenous and exogenous stem cells for lung therapy are being characterized by defining developmental lineages, surface marker expression, functions within the lung and responses to injury and disease. Seeding decellularized lung tissue or bioengineered matrices with various stem and progenitor cells is an approach that has already been used to replace bronchus and trachea in human patients and awaits further development for whole lung tissue.
Areas of agreement
Cellular therapies have clear potential for respiratory disease. However, given the surface size and complexity of lung structure, the probability of a single cellular population sufficing to regenerate the entire organ, as in the bone marrow, remains low. Hence, lung regenerative medicine is currently focused around three aims: (i) to identify and stimulate resident cell populations that respond to injury or disease, (ii) to transplant exogenous cells which can ameliorate disease and (iii) to repopulate decellularized or bioengineered lung matrix creating a new implantable organ.
Areas of controversy
Lack of consensus on specific lineage markers for lung stem and progenitor cells in development and disease constrains transferability of research between laboratories and sources of cellular therapy. Furthermore, effectiveness of individual cellular therapies to correct gas exchange and provide other critical lung functions remains unproven. Finally, feasibility of autologous whole organ replacement has not been confirmed as a durable therapy.
Growing points
Cellular therapies for lung regeneration would be enhanced by better lineage tracing within the lung, the ability to direct differentiation of exogenous stem or progenitor cells, and the development of functional assays for cellular viability and regenerative properties. Whether endogenous or exogeneous cells will ultimately play a greater therapeutic role remains to be seen. Reducing the need for lung replacement via endogenous cell-mediated repair is a key goal. Thereafter, improving the potential of donor lungs in transplant recipients is a further area where cell-based therapies may be beneficial. Ultimately, lung replacement with autologous tissue-engineered lungs is another goal for cell-based therapy.
Areas timely for developing research
Defining ‘lung stem or progenitor cell’ populations in both animal models and human tissue may help. Additionally, standardizing assays for assessing the potential of endogenous or exogenous cells within the lung is important. Understanding cell–matrix interactions in real time and with biomechanical insight will be central for lung engineering.
Cautionary note
Communicating the real potential for cell-based lung therapy needs to remain realistic, given the keen expectations of patients with end-stage lung disease.
doi:10.1093/bmb/ldr051
PMCID: PMC3695661  PMID: 22279079
endogenous lung stem cells; exogenous stem cells; lung regeneration and repair; regenerative medicine; stem cell therapies
5.  Occupational activities and osteoarthritis of the knee 
British medical bulletin  2012;102:147-170.
Background
The prevalence of knee osteoarthritis (OA) is rising and the search for interventions to mitigate risk is intensifying. This review considers the contribution of occupational activities to disease occurrence and the lessons for prevention.
Sources
Systematic search in Embase and Medline covering the period 1996 to November 2011.
Areas of agreement
Reasonably good evidence exists that physical work activities (especially kneeling, squatting, lifting, and climbing) can cause and/or aggravate knee OA. These exposures should be reduced where possible. Obese workers with such exposures are at additional risk of knee OA and should therefore particularly be encouraged to lose weight.
Areas of uncertainty/research need
Workplace interventions and policies to prevent knee OA have seldom been evaluated. Moreover, their implementation can be problematic. However, the need for research to optimise the design of work in relation to knee OA is pressing, given population trends towards extended working life.
doi:10.1093/bmb/lds012
PMCID: PMC3428837  PMID: 22544778
Gonarthrosis; employment; occupational; aetiology
6.  The older worker with osteoarthritis of the knee 
British medical bulletin  2012;102:79-88.
Background
Changing demographics mean that many patients with large joint arthritis will work beyond traditional retirement age. This review considers the impact of knee osteoarthritis (OA) on work participation and the relation between work and knee replacement (TKR).
Sources
Two systematic searches in Embase and Medline, supplemented by three systematic reviews.
Areas of agreement
Probably, although evidence is limited, knee OA considerably impairs participation in work (labour force participation, work attendance and work productivity).
Areas of uncertainty/research need
Little is known about effective interventions (treatments, work changes and policies) to improve vocational participation in patients with knee OA; or how type of work affects long-term clinical outcomes (e.g. pain, function, the need for revision surgery) in patients with TKRs. The need for such research is pressing and opportune, as increasing numbers of patients with knee OA or TKR expect to work on.
doi:10.1093/bmb/lds011
PMCID: PMC3428873  PMID: 22544779
Gonarthrosis; employment; occupational; management; work participation
7.  Management of trypanosomiasis and leishmaniasis 
British Medical Bulletin  2012;104(1):175-196.
Background
The current treatments for human African trypanosomiasis (HAT), Chagas disease and leishmaniasis (collectively referred to as the kinetoplastid diseases) are far from ideal but, for some, there has been significant recent progress. For HAT the only advances in treatment over the past two decades have been the introduction of an eflornithine/nifurtimox co-administration and a shorter regime of the old standard melarsoprol.
Sources of data
PubMed.
Areas of Agreement
There is a need for new safe, oral drugs for cost-effective treatment of patients and use in control programmes for all the trypanosomatid diseases.
Areas of controversy
Cutaneous leishmaniasis is not on the agenda and treatments are lagging behind.
Growing points
There are three compounds in development for the treatment of the CNS stage of HAT: fexinidazole, currently due to entry into phase II clinical studies, a benzoxaborole (SCYX-7158) in phase I trials and a diamidine derivative (CPD-0802), in advanced pre-clinical development. For Chagas disease, two anti-fungal triazoles are now in clinical trial. In addition, clinical studies with benznidazole, a drug previously recommended only for acute stage treatment, are close to completion to determine the effectiveness in the treatment of early chronic and indeterminate Chagas disease. For visceral leishmaniasis new formulations, therapeutic switching, in particular AmBisome, and the potential for combinations of established drugs have significantly improved the opportunities for the treatment in the Indian subcontinent, but not in East Africa.
Areas timely for developing research
Improved diagnostic tools are needed to support treatment, for test of cure in clinical trials and for monitoring/surveillance of populations in control programmes.
doi:10.1093/bmb/lds031
PMCID: PMC3530408  PMID: 23137768
human African trypanosomiasis; Chagas disease; leishmaniasis; antiprotozoal drug treatment; antiprotozoal drug development
8.  TARGETED THERAPIES FOR PANCREATIC CANCER 
British medical bulletin  2008;87:97-130.
Introduction
Pancreatic cancer is a devastating malignancy and a leading cause of cancer mortality. Furthermore, early diagnosis represents a serious hurdle for clinicians as symptoms are non-specific and usually manifest in advanced, treatment-resistant stages of the disease.
Sources of data
Here, we review the rationale and progress of targeted therapies currently under investigation.
Areas of agreement
At present, chemoradiation regimes are administered palliatively, and produce only marginal survival benefits, underscoring a desperate need for more effective treatment modalities.
Areas of controversy
Questions have been raised as to whether erlotinib, the only targeted therapy to attain a statistically significant increase in median survival, is cost-effective.
Growing points
The last decade of research has provided us with a wealth of information regarding the molecular nature of pancreatic cancer, leading to the identification of signalling pathways and their respective components which are critical for the maintenance of the malignant phenotype.
Areas timely for developing research
These proteins thus represent ideal targets for novel molecular therapies which embody an urgently needed novel treatment strategy.
doi:10.1093/bmb/ldn027
PMCID: PMC2882225  PMID: 18753179
Pancreatic cancer; targeted therapy; novel therapy; clinical trials
9.  Dopamine cell transplantation in Parkinson's disease: challenge and perspective 
British Medical Bulletin  2011;100(1):173-189.
Background
Functional imaging provides a valuable adjunct to clinical evaluation for assessing the efficacy of cell-based restorative therapies in Parkinson's disease (PD).
Sources of data
In this article, we review the latest advances on the use of positron emission tomography (PET) imaging in evaluating the surgical outcome of embryonic dopamine (DA) cell transplantation in PD patients.
Areas of agreement
These studies suggest long-term cell survival and clinical benefit following striatal transplantation of fetal nigral tissue in PD patients and in models of experimental parkinsonism.
Areas of controversy
Adverse events subsequent to transplantation have also been noted and attributed to a variety of causes.
Growing points
Optimal outcomes of DA cell transplantation therapies are dependent on tissue composition and phenotype of DA neurons in the graft.
Areas timely for developing research
Given continued progress in DA neuron production from stem cells in recent years, transplantation of neural stem cells may be the next to enter clinical trials in patients.
Conclusion
The existing data from studies of embryonic DA transplantation for advanced PD have provided valuable insights for the design of new cell-based therapies for the treatment of this and related neurodegenerative disorders.
doi:10.1093/bmb/ldr040
PMCID: PMC3276236  PMID: 21875864
cell transplantation; Parkinson's disease; regenerative medicine; emission tomography
10.  Musculoskeletal diseases—tendon 
British Medical Bulletin  2011;99(1):211-225.
Introduction
Tendons establish specific connections between muscles and the skeleton by transferring contraction forces from skeletal muscle to bone thereby allowing body movement. Tendon physiology and pathology are heavily dependent on mechanical stimuli. Tendon injuries clinically represent a serious and still unresolved problem since damaged tendon tissues heal very slowly and no surgical treatment can restore a damaged tendon to its normal structural integrity and mechanical strength. Understanding how mechanical stimuli regulate tendon tissue homeostasis and regeneration will improve the treatment of adult tendon injuries that still pose a great challenge in today's medicine.
Source of data
This review summarizes the current status of tendon treatment and discusses new directions from the point of view of cell-based therapy and regenerative medicine approach. We searched the available literature using PubMed for relevant original articles and reviews.
Growing points
Identification of tendon cell markers has enabled us to study precisely tendon healing and homeostasis. Clinically, tissue engineering for tendon injuries is an emerging technology comprising elements from the fields of cellular source, scaffold materials, growth factors/cytokines and gene delivering systems.
Areas timely for developing research
The clinical settings to establish appropriate microenvironment for injured tendons with the combination of these novel cellular- and molecular-based scaffolds will be critical for the treatment.
doi:10.1093/bmb/ldr025
PMCID: PMC3202301  PMID: 21729872
tendon injury; tissue engineering; regenerative medicine; stem cells; scleraxis; mechanical force
11.  Cardiac cell therapy: where we've been, where we are, and where we should be headed 
British Medical Bulletin  2011;98(1):161-185.
Introduction
Stem cell therapy has emerged as a promising strategy for the treatment of ischemic cardiomyopathy.
Sources of data
Multiple candidate cell types have been used in preclinical animal models and in clinical trials to repair or regenerate the injured heart either directly (through formation of new transplanted tissue) or indirectly (through paracrine effects activating endogenous regeneration).
Areas of agreement
(i) Clinical trials examining the safety and efficacy of bone marrow derived cells in patients with heart disease are promising, but results leave much room for improvement. (ii) The safety profile has been quite favorable. (iii) Efficacy has been inconsistent and, overall, modest. (iv) Tissue retention of cells after delivery into the heart is disappointingly low. (v) The beneficial effects of adult stem cell therapy are predominantly mediated by indirect paracrine mechanisms.
Areas of controversy
The cardiogenic potential of bone marrow-derived cells, the mechanism whereby small numbers of poorly-retained cells translate to measurable clinical benefit, and the overall impact on clinical outcomes are hotly debated.
Growing points/areas timely for developing research
This overview of the field leaves us with cautious optimism, while motivating a search for more effective delivery methods, better strategies to boost cell engraftment, more apt patient populations, safe and effective ‘off the shelf’ cell products and more potent cell types.
doi:10.1093/bmb/ldr018
PMCID: PMC3149211  PMID: 21652595
stem cell therapy; cardiac stem cells; heart regeneration
12.  Cochlear Implants and Brain Plasticity 
British medical bulletin  2002;63:183-193.
Cochlear implants have been implanted in over 110,000 deaf adults and children worldwide and provide these patients with important auditory cues necessary for auditory awareness and speech perception via electrical stimulation of the auditory nerve (AN). In 1942 Woolsey & Walzl presented the first report of cortical responses to localised electrical stimulation of different sectors of the AN in normal hearing cats, and established the cochleotopic organization of the projections to primary auditory cortex. Subsequently, individual cortical neurons in normal hearing animals have been shown to have well characterized input-output functions for electrical stimulation and decreasing response latencies with increasing stimulus strength. However, the central auditory system is not immutable, and has a remarkable capacity for plastic change, even into adulthood, as a result of changes in afferent input. This capacity for change is likely to contribute to the ongoing clinical improvements observed in speech perception for cochlear implant users. This review examines the evidence for changes of the response properties of neurons in, and consequently the functional organization of, the central auditory system produced by chronic, behaviourally relevant, electrical stimulation of the AN in profoundly deaf humans and animals.
PMCID: PMC1988843  PMID: 12324393
Electrical Stimulation; Auditory Cortex; Plasticity; Cochleotopy; Reorganisation

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