The virtual fracture clinic: Reducing unnecessary review of clavicle fractures.

INTRODUCTION: We re-designed the outpatient management of trauma at our institution to eliminate appointments if there would be no change in management or information provision. All cases referred by the Emergency Department (ED) were reviewed at a Virtual Fracture Clinic (VFC) by an orthopaedic consultant and telephoned afterwards by a senior nurse. If face-to-face review was required, it was arranged at a specialist shoulder clinic. AIMS: The primary aim of this study was to evaluate the proportion of clavicle fractures that could be discharged without physical review. The secondary aim was to assess the patient reported functional outcome and satisfaction among patients who were discharged without further review. PATIENTS AND METHODS: A retrospective review was performed of patients who attended the ED with a clavicle fracture between October 2011 and September 2012. 138 patients were included. The number of patients who were discharged without a physical review was analysed. All radiographs were classified according to the Robinson classification. We recorded the number of undisplaced/minimally-displaced fractures that were discharged virtually. The number of patients with a displaced midshaft fracture who were seen at a specialist clinic was also recorded. A questionnaire was sent to all patients at one year post-injury to evaluate their outcome (QuickDASH and EQ-5D) and satisfaction with the new service. RESULTS: 62/138 (45%) were directly discharged from the VFC. The majority of virtual discharges occurred in the undisplaced fracture types (84% versus 13%, RR 6.4, 95% CI 3.5-11.5). 78% patients responded to the questionnaires. 91% of patients were satisfied with their recovery from the injury. 86.4% patients were satisfied with the information provided regarding their treatment. In the virtually discharged group the mean EQ-5D VAS was 78.1 (EQ5D range 0.06-1, SD 0.248). The mean Quick DASH score was 16.1(SD 25.2). CONCLUSIONS: Virtual discharge of undisplaced clavicle fractures is appropriate and results in acceptable clinical outcomes and patient satisfaction. This redesigned process has significant benefits for patients as there were far fewer hospital visits by avoiding unnecessary appointments. The orthopaedic service also benefited by having more time available for the management of complex cases.

The commitment of human cells to senescence.

Fifty years ago, it was demonstrated by Leonard Hayflick that human diploid fibroblasts grown in culture have a finite lifespan. Since that time, innumerable experiments have been published to discover the mechanism(s) that are responsible for this 'Hayflick limit' to continuous growth. Much new information has been gained, but there are certain features of this experimental system which have not been fully understood. One is the fact that different populations of the foetal lung strains WI-38 and MRC-5 have a range in division potential of at least a millionfold. The commitment theory of cellular aging, published more than 30 years ago, is able to explain this, but it has been consistently ignored. The theory predicts that bottlenecks, which are transient reductions in population size, can significantly reduce lifespan, or increase variability of lifespans. Computer simulations specify the effects of bottlenecks on longevity, and these were confirmed in two series of experiments. Commitment to senescence may be the loss of telomerase, which leads to the erosion of telomeres and the inability to grow indefinitely. Many experiments have been done with skin fibroblasts from human donors of different age, and it was originally thought that in vitro lifespan was inversely correlated with donor age. In these experiments, a single skin biopsy produces a population of cells that are grown to senescence. However, there is no reason to believe that skin fibroblasts are less variable in their in vitro lifespan than foetal lung strains, in which case the data points with skin cells are so variable that they may completely obscure any inverse correlation between culture lifespans and donor age.

Telomeres and telomerase: the commitment theory of cellular ageing revisited.

It is not always realised that separate fibroblast populations of the same strain have very different lifespans, that is, over a million-fold range. This is best documented for human strains WI-38 and MRC-5. There is evidence that it is the molecular clock of telomere shortening which determines the growth potential of these cells. However, if a clock is set and runs its course one would expect parallel cultures to have similar lifespans. The commitment theory of fibroblast ageing proposes that commitment occurs during early cell divisions with a given probability and after that there is then a constant number of divisions until growth ceases. This constant number could be determined by the gradual loss of telomeres. The stochastic feature of the theory is the probability of the loss of the last uncommitted cells or the youngest committed cells. These cells have the longest lifespan and will give rise to the final population.

The recombination, repair and modification of DNA.

This article is an overview of the author's involvement in theoretical and experimental research on genetic recombination and DNA repair, and also on the enzymic modification of cytosine in DNA to 5-methyl cytosine. It includes the history of the discovery of the central intermediate in genetic recombination at the DNA level, and the repair of mismatched bases. These explain the major features of genetic fine structure. The first repair and recombination defective mutants in any eukaryote were isolated in the smut fungus Ustilago maydis. The hypothesis that DNA methylation has a role in gene expression in higher organism is now supported by abundant evidence. Direct evidence that gene silencing in mammalian cells is causally related to DNA methylation has been obtained.

Longevity mutants do not establish any "new science" of ageing.

The biological reasons for ageing are now well known, so it is no longer an unsolved problem in biology. Furthermore, there is only one science of ageing, which is continually advancing. The significance and importance of the mutations that lengthen the lifespan of invertebrates can be assessed only in relationship to previous well-established studies of ageing. The mutant strains of model organisms that increase longevity have altered nutrient signalling pathways similar to the effects of dietary restriction, and so it is likely that there is a shift in the trade-off between reproduction and maintenance of the soma. To believe that the isolation and characterisation of a few invertebrate mutations (as well as those in yeast) will "galvanise" the field and provide new insights into human ageing is an extreme point of view which does not recognize the huge progress in ageing research that has been made in the last 50 years or so.

The extreme arrogance of anti-aging medicine.

The anti-aging medicine movement proposes to alter the human body in order to achieve extreme longevity. To do this it has to reverse or by-pass the multiple causes of human aging. These include a large number of age-associated pathologies, each of which is being studied in great detail in research laboratories around the world. The protagonists of anti-aging medicine claim that it will be far more successful than the combined efforts of the innumerable scientists carrying out this research. Aging has an extremely long evolutionary history, and the anatomical structure and physiology of animals is directly related to their finite lifespan. The anti-aging movement proposes in a few decades to reverse what has been the result of millions of years of evolution.

The homologous recombination system of Ustilago maydis.

Homologous recombination is a high fidelity, template-dependent process that is used in repair of damaged DNA, recovery of broken replication forks, and disjunction of homologous chromosomes in meiosis. Much of what is known about recombination genes and mechanisms comes from studies on baker's yeast. Ustilago maydis, a basidiomycete fungus, is distant evolutionarily from baker's yeast and so offers the possibility of gaining insight into recombination from an alternative perspective. Here we have surveyed the genome of U. maydis to determine the composition of its homologous recombination system. Compared to baker's yeast, there are fundamental differences in the function as well as in the repertoire of dedicated components. These include the use of a BRCA2 homolog and its modifier Dss1 rather than Rad52 as a mediator of Rad51, the presence of only a single Rad51 paralog, and the absence of Dmc1 and auxiliary meiotic proteins.

Towards understanding the extreme radiation resistance of Ustilago maydis.

Ustilago maydis is a phytopathogenic fungus exhibiting extreme resistance to UV and ionizing radiation. The molecular mechanisms underlying this resistance are as yet unknown. The recently determined genome sequence was examined for clues to the radiation resistance, focusing on proteins in homologous recombination, but there was little that was unusual about them. Furthermore, by comparison, its recombinational repair system seems to be only minimally related to the extended synthesis-dependent DNA strand-annealing system of Deinococcus radiodurans. Thus, consideration should be given to the possibility that incremental structural changes in repair proteins or their elevated expression are the basis for the extreme radiation resistance in U. maydis. Evolution of a system enabling the survival of U. maydis under such conditions could be a secondary consequence of adaptation to an environment of continual genotoxic stress encountered in its habitat.

Physics and the origins of molecular biology.

Bohr, Delbrück and Schrödinger were physicists who had important influences on biology in the second half of the twentieth century. They thought that future studies of the gene might reveal new principles or paradoxes, analogous to the wave/particle paradox of light propagation, or even new physical laws. This stimulated several physicists to enter the field of biology. Delbrück founded the bacteriophage group which provided one of the roots of molecular biology. Another was X-ray crystallography which led to the discovery of DNA structure. The strength and success of molecular biology came from the many interactions between geneticists, physicists, chemists and biochemists. It was also characterized by a powerful combination of theoretical and experimental approaches.

Meiosis and sex: potent weapons in the competition between early eukaryotes and prokaryotes.

The earliest eukaryote species almost certainly evolved in an environment dominated by numerous prokaryotic species. If the first eukaryotic cells were larger and grew more slowly than their prokaryotic neighbours, they might well have been at a competitive disadvantage. It is proposed here that the early evolution of meiosis, with its capacity for generating new favourable gene combinations, might have served to offset any such competitive disadvantages. Meiosis and sex could have arisen in an asexually reproducing species and formed a clonal population.

Aging is no longer an unsolved problem in biology.

For much of the 20th century, the accumulation of a considerable amount of information about the processes of aging did not reveal the underlying mechanisms. Toward the end of that century, the biological basis for aging became very much clearer. It became apparent that the best strategy for animals' survival was to develop to an adult, but not to invest resources in maintaining the body, or soma, indefinitely. In their natural environment, animals do not survive environmental hazards (predators, disease, starvation, and drought) to reach a long life span. There is thus a trade-off between the investment of resources in reproduction, and the survival time of the soma. At a stroke, this solves the problem of different rates of aging in different species, because those that develop and reproduce fast also have short life spans, and those that develop and reproduce slowly have long life spans. This difference is due to actual resources invested in the maintenance of the adult soma. There is now much evidence that long-lived mammals have much more efficient maintenance mechanisms than short-lived mammals. Thus, aging can be defined as the eventual failure of maintenance. It also became apparent that many different maintenance mechanisms exist, and that these depend on very many genes and a considerable investment in metabolic resources. Most individual theories of aging revolve around the failure of a given maintenance system, but as there are many of these, it is likely that most of the important theories have some degree of truth. A broad interpretation of the different degenerative changes during senescence should therefore be adopted, with the major conclusion that aging is multicausal. It is also evident that the evolved design of many components of complex animals is incompatible with indefinite survival. We can therefore conclude that this evolved design is intrinsically related to the fact of aging. This in turn means that aging cannot be reversed, although it may be modulated, as, for example, by calorie restriction.

Food, fertility and longevity.

Some animals live in environments in which the food supply fluctuates. When it is scarce these animals do not breed, but invest resources into survival until food is again available, and they can reproduce. Under these circumstances the lifespan can be increased, just as it is after calorie restriction. Other animals have a fairly constant food supply, and it is predicted that these would not have an extended life span if subjected to calorie restriction. Hibernation is a natural form of calorie restriction, and in some cases may lengthen lifespan.

John Robert Stanley Fincham: 11 August 1926 - 9 February 2005.

Professor John Fincham was one of the UK's leading geneticists, with a remarkably broad knowledge of the subject across the biological kingdoms. He became an international leader through being at the forefront of microbial genetics as some of the founding principles of the relationships between gene structure, activity and enzyme functions were being uncovered. He spearheaded discoveries from the one gene-one enzyme concept, through genetic complementation, protein structure and recombination. Much of his experimental microbial research centered on the genetic and enzyme variants of glutamate dehydrogenase in the fungus Neurospora. He also brought his outstanding mind and comprehensive interest in genetics to the then obscure features of unstable genes and transposable elements in plants. His standing was recognized by holding prestigious chairs in Leeds, Edinburgh and Cambridge universities. He was a talented writer, producing several textbooks and especially the leading text Fungal genetics. He was also a practitioner and lover of sports and in his early career was politically active. His successes in life made him an extraordinarily talented man who achieved much as a leader in genetics in the UK and internationally.

Epigenetics: a historical overview.

In the first half of the twentieth century, developmental biology and genetics were separate disciplines. The word epigenetics was coined by Waddington to link the two fields. Epigenetics could be broadly defined as the sum of all those mechanisms necessary for the unfolding of the genetic programme for development. Several decades later specific mechanisms were proposed in which information was superimposed on DNA sequences. In particular, it was suggested that 5-methyl cytosine had a role in controlling gene expression, and also that the pattern of methylation was heritable. These predictions are now supported by a large body of evidence which shows that methylation is strongly associated with gene silencing in a variety of biological contexts. There are now also many examples of epigenetic inheritance through the germ line There are several other important epigenetic mechanisms involving chromatin and histone modifications, and also the expanding field of regulatory RNAs. The human epigenome project will unravel the pattern of DNA methylation in different tissues, and will this determine whether the regulation of gene expression is at the level of DNA or chromatin, or both.

Ageing and the extinction of large animals.

In the modulation of longevity by natural selection there is a trade-off between the investment of resources in the maintenance of the body, or soma, and the investment in reproduction. There is accumulating evidence that long-lived mammalian species have much more efficient maintenance than short-lived ones. It is also clear that short-lived ground-living mammalian species reproduce very much more quickly than larger long-lived species, and in all mammals there is an inverse relationship between maximum reproductive potential and maximum longevity. These features of life-history strategies very strongly support the disposable soma theory of the evolution of ageing. Slow development and large size are associated with delayed ageing. If the environment changes, for whatever reason, small rapidly breeding species are able to adapt and survive much more easily that large slow breeding species. This can explain the very well documented extinction of many large mammalian species during the Pleistocene. In an environment which remains constant for a long period of time, selection favours the evolution of larger species, but these are put at risk if the environment becomes less favorable. Fluctuating environments are more likely to promote the evolution of small short-lived species with high fecundity.