Editor’s Choice
Editor-in-Chief
The British Medical Bulletin has considerably increased the number of Commissioning Editors over the past year, until now it has 36; these are to be found on the web page, together with the names of the Editorial Advisory Committee.
This broadening of its commissioning base is reflected in a widening of the topics that we publish, all of which are placed online, before being gathered into the paper edition. This edition reflects the broad base with a range of topics from highly specialist approaches, to practical, but all from people working at the forefront of their own speciality.
The first of these by Johan Aschan at the Karolinska in Sweden is on allogeneic haematopoietic stem cell transplantation (HSCT) (page 23).
He says that this approach is now an established treatment of haematological malignancies and other immunohaematopoietic disorders. The use of unrelated donors and cord blood grafts has increased the possibilities of finding a suitable donor, and results are approaching those with sibling donor transplants. He goes on to say that using peripheral blood stem cells, instead of bone marrow, results in faster engraftment but at an increased risk of chronic graft-versus-host disease. Early detection of minimal residual disease or recurrent recipient haematopoietic cells is important to initiating early intervention with immunotherapy. There are new hopes for using donor lymphocyte infusions, which have not only an anti-leukaemic effect but also an anti-tumour effect against some solid organ tumours, including metastatic solid tumours. In addition, mesenchymal stem cells may improve the success of grafts and have immunomodulatory effects.
A largely theoretical paper, from Dr Andrew Gennery in Newcastle-upon-Tyne, is on ‘Primary immunodeficiency syndromes associated with defective DNA double-strand break repair’ (page 71).
He describes how ionizing radiation exposure can cause DNA double-strand breaks potentially leading to cell death or carcinogenesis. Non-homologous end-joining is thought to be the main repair pathway, and many repair pathway proteins have been identified. Diverse lymphocyte receptors have evolved to identify potential pathogens by breaking and randomly re-sorting the gene segment coding for antigen receptors. Individuals with defective repair pathways are increasingly recognized with radiosensitivity and immunodeficiency. Thus, patients with defects in ataxia-telangiectasia mutated, nibrin, MRE11, Rad50, Artemis, DNA ligase IV and Cernunnos-XRCC4-like factor have been identified. Most exhibit immunodeficiency, with a spectrum of presentation and overlap between conditions. Conventional treatment with immunoglobulin replacement or HSCT can be effective. A greater understanding of the molecular defects will enable better, tailored therapies to improve survival.
The next three papers are on the treatment of relatively rare diseases, at least in this country. The first of these, written by Professor Inderjeet Dokal from the Academic Unit of Paediatrics in Barts, the London and St Mary’s, is on Fanconi’s anaemia and related bone marrow failure syndromes (page 37).
He makes the point that the inherited bone marrow failure syndromes are a heterogeneous group of disorders, usually in association with one or more somatic abnormalities. The bone marrow failure may present at birth or at a variable time thereafter up to adulthood. Over the last decade, there have been significant advances in the genetics of these syndromes, particularly Fanconi’s anaemia and dyskeratosis congenita. These advances are beginning to provide a better understanding of normal haemopoiesis and of the pathophysiology of some cases of idiopathic aplastic anaemia. They have also provided important insights into some aspects of DNA repair (FA/BRCA pathway) and telomere maintenance (DC-related genes), two pathways critical in the maintenance of genomic stability. These advances are already facilitating better diagnosis of patients with these disorders. It is hoped that they will also form the basis for developing new treatments.
The next review, by David Kavanagh, Timothy Goodship and Anna Richards from a nice combination of St Louis in the United States and Newcastle-upon-Tyne, is on atypical haemolytic uraemic syndrome (HUS) (page 5).
They show that HUS is characterized by the triad of thrombocytopenia, microangiopathic haemolytic anaemia and acute renal failure. It may be classified as either diarrhoeal-associated or non-diarrhoeal/atypical. Non-diarrhoeal/atypical disease has recently been shown to be a disease of complement dysregulation, with 50% of cases involving the complement regulatory genes, factor H (CFH), membrane cofactor protein (MCP; CD46) and factor I (IF). However, incomplete penetrance of mutations in each of these genes is reported. This suggests that a precipitating event or trigger is required to unmask the complement regulatory deficiency. The reported precipitating events predominantly cause endothelial injury. Discovery of these mutations has revealed important genotype–phenotype correlations. MCP-HUS has a better prognosis and a better outcome after transplantation than either CFH-HUS or IF-HUS.
The next disease, uncommon in this country, but common in many developing countries, is reviewed by Steve Walker and Diana Lockwood from the London School of Hygiene and Tropical Medicine in London on the clinical and immunological features of leprosy (page 103).
They make the point that leprosy, a granulomatous disease affecting the skin and nerves caused by Mycobacterium leprae, continues to be a significant public health problem internationally. Multidrug therapy (MDT) cures the infection, but immunological reactions may occur, and neuropathy may lead to disability and deformity. It is important that the manifestations of the condition are recognized as early as possible so that nerve damage can be identified and treated rapidly. The review is a most useful overview, including a section on the complexity of leprosy in the presence of HIV infection.
We next have two reviews on highly disabling diseases. The first of these from Jesse Dawson and Matthew Walters at the Stroke Unit at the University of Glasgow is on new and emerging treatments for stroke (page 87).
They state that acute stroke, although the main cause of major disability in the United Kingdom, is a treatable condition. They point to the gross deficiencies in the treatment of the disease in Britain. Over the last 10 years, the benefit of many acute strategies has become established, and the evaluation of other potentially beneficial interventions is underway. The review discusses the evidence-based management of acute stroke patients, considers barriers to the provision of such care and updates readers on emergent strategies, which may form part of stroke management in the future. They emphasize the importance of brain scanning. It also contains an important section on neuroprotectant strategies for stroke.
The next, by Gordon Waddell, in Cardiff, is on preventing incapacity in people with musculoskeletal disorders (page 55).
He shows that musculoskeletal disorders are among the most common causes of sickness absence, long-term incapacity for work and ill-health retirement. The number of Incapacity Benefit recipients in the United Kingdom has trebled since 1979, despite improvement in objective measures of health. Most of the trend is in non-specific conditions (largely subjective complaints, often with little objective pathology or impairment). Understanding such incapacity requires a biopsychosocial model that addresses all the physical, psychological and social factors involved in human illness and disability. Rehabilitation should be directed to overcoming biopsychosocial obstacles to recovery and return to work. These principles are fundamental to better clinical and occupational management and minimizing incapacity. Sickness absence and incapacity from non-specific musculoskeletal conditions could be reduced by 33–50%, but that depends on a fundamental shift in thinking about these conditions—in health care, in the workplace and in society.
The last review is, in many ways, the most important for the danger presented to world health. This, by Robert West at University College, London, is on tobacco control: present and future (page 123).
He says that the history of tobacco control in the twentieth century can be summed up by the phrase ‘too little, too late’. The century saw the proliferation of the most deadly form of tobacco use: cigarette smoking. Until the 1970s, no government took serious action to protect its citizens. He makes the point that probably the most effective global tobacco control ‘strategies’ to date have not been motivated by health concerns: they have been inaccessible or uneconomic markets for tobacco companies and a cultural taboo on women smoking. Economic development has led to massive increases in male cigarette smoking in developing countries, but even now <10% of women in non-Western countries such as China, Russia and India smoke. With ‘westernization’, this picture is changing. Without drastic action to get current smokers to stop, the annual rate of tobacco-related deaths will grow from 5 million in 2006 to 10 million in 2025. Without further action to prevent the take-up of smoking, the subsequent death toll will be even higher. The recently enacted World Health Organization (WHO)-initiated Framework Convention on Tobacco Control (FCTC) can mitigate this impending disaster but only if it is implemented according to the spirit and not just the letter of its articles. Specific tobacco levies in every country should be the primary means of kick-starting the process, with the proceeds being used exclusively to fund other tobacco control initiatives, including product regulation.
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Related articles in BMB:
- Allogeneic haematopoietic stem cell transplantation: current status and future outlook
- Johan Aschan
BMB 2006 77-78: 23-36.[Abstract] [FREE Full Text] - Primary immunodeficiency syndromes associated with defective DNA double-strand break repair
- A. R. Gennery
BMB 2006 77-78: 71-85.[Abstract] [FREE Full Text] - Fanconi’s anaemia and related bone marrow failure syndromes
- Inderjeet Dokal
BMB 2006 77-78: 37-53.[Abstract] [FREE Full Text] - Atypical haemolytic uraemic syndrome
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BMB 2006 77-78: 103-121.[Abstract] [FREE Full Text] - New and emerging treatments for stroke
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