Molecular Medicine and Molecular Pathology for Hematologists:II. Lets go Techno; Principles of the Molecular Technologies and their Applications in Haematology

Molecular techniques have a key role to play in laboratory and clinical haematology. Restriction enzymes allow nucleic acids to be reduced in size for subsequent analysis. In addition they allow selection of specific DNA or RNA sequences for cloning into bacterial plasmids. These plasmids are naturally occuring DNA molecules which reside in bacterial cells. They can be manipulated to act as vehicles or carriers for biologically and medically important genes, allowing the production of large amounts of cloned material for research purposes or to aid in the production of medically important recombinant molecules such as insulin. As acquired or inherited genetic changes are implicated in a wide range of haematological diseases, it is necessary to have highly specific and sensitive assays to detect these mutations. Most of these techniques rely on nucleic acid hybridisation, benefitting from the ability of DNA or RNA to bind tighly to complimentary bases in the nucleic acid structure. Production of artificial DNA molecules called probes permits nucleic acid hybridiation assays to be performed, using the techniques of southern blotting or dot blot analysis. In addition the base composition of any gene or region of DNA can be determined using DNA sequencing technology. The advent of the polymerase chain reaction (PCR) has revolutionised all aspects of medicine, but has particular relevance in haematology where easy access to biopsy material provides a wealth of material for analysis. PCR permits quick and reliable manipulation of sample material and its ability to be automated makes it an ideal tool for use in the haematology laboratory.

Molecular Medicine and Molecular Pathology for Haematologists:I. Gene Speak made Easy: An Overview of Genes and Gene Expression

Molecular Medicine and Molecular Pathology are integral parts of Haematology as we enter the new millennium. Their origins can be linked to fundamental developments in the basic sciences, particularly genetics, chemistry and biochemistry. The structure of DNA and the genetic code that it encrypts are the critical starting points to our understanding of these new disciplines. The genetic alphabet is a simple one, consisting of just 4 letters, buts its influence is crucial to human development and differentiation. The concept of a gene is not a new one but the Human Genome Project (a joint world-wide effort to characterise our entire genetic make-up) is providing an invaluable understanding of how genes function in normal cellular processes and pinpointing how disruption of these processes can lead to disease. Transcription and translation are the key events by which our genotype is converted to our phenotype (via a messenger RNA intermediate), producing the myriad proteins and enzymes which populate the cellular factory of our body. Unlike the bacterial or prokaryotic genome, the human genome contains a large amount of non coding DNA (less than 1% of our genome codes for proteins), and our genes are interrupted, with the coding regions or exons separated by non coding introns. Precise removal of the intronic material after transcription (though a process called splicing) is critical for efficient translation to occur. Incorrect splicing can lead to the generation of mutant proteins, which can have a dilaterious effect on the phenotype of the individual. Thus the 100,000-200,000 genes which are present in each cell in our body have a defined control mechanism permitting efficient and appropriate expression of proteins and enzymes and yet a single base change in just one of those genes can lead to diseases such as haemophilia or fanconis anaemia.

Street Medicine – Assessment Work Strategies of Paramedics on the Front lines of Emergency Health Services

This article is based on an institutional ethnographic inquiry into the work of paramedics and the institutional setting that organizes and coordinates their work processes in a major City in Canada. Drawing on over 200 hours of observations and over 100 interviews with paramedics (average length of 18 minutes) and other emergency medical personnel, this article explores the standard and not so standard work of paramedics as they assess and care for their patients on the front lines of emergency health services. The multiplicity of interfacing social, demographic, locational, and situational factors that shape and organize the work of paramedics are analyzed. In doing so, this article provides insights into the complex work of an understudied yet ever-important profession in healthcare.

Automating fault tolerance in high-performance computational biological jobs using multi-agent approaches

Background: Large-scale biological jobs on high-performance computing systems require manual intervention if one or more computing cores on which they execute fail. This places not only a cost on the maintenance of the job, but also a cost on the time taken for reinstating the job and the risk of losing data and execution accomplished by the job before it failed. Approaches which can proactively detect computing core failures and take action to relocate the computing core's job onto reliable cores can make a significant step towards automating fault tolerance. Method: This paper describes an experimental investigation into the use of multi-agent approaches for fault tolerance. Two approaches are studied, the first at the job level and the second at the core level. The approaches are investigated for single core failure scenarios that can occur in the execution of parallel reduction algorithms on computer clusters. A third approach is proposed that incorporates multi-agent technology both at the job and core level. Experiments are pursued in the context of genome searching, a popular computational biology application. Result: The key conclusion is that the approaches proposed are feasible for automating fault tolerance in high-performance computing systems with minimal human intervention. In a typical experiment in which the fault tolerance is studied, centralised and decentralised checkpointing approaches on an average add 90% to the actual time for executing the job. On the other hand, in the same experiment the multi-agent approaches add only 10% to the overall execution time

The Dublin Lock Hospital: Medicine, Morality, Disease and Sin

Anecdotal evidence has it that when Dublin’s venereal disease hospital closed its doors for the last time in the 1950s, its administrative staff began to burn its records, starting with the most recent. This attempt to conceal the results of sexual profligacy is perhaps understandable in the rarefied climate of mid-century Catholic Ireland. However, the sense of shame attached to this institution has been pervasive. For example, of all Dublin’s major hospitals, the lock hospital remains the only one without a dedicated history. And, throughout its two centuries of existence, the ‘lock’ had often been a site of controversy and approbation.

The institution began in the eighteenth century as the most peripatetic, poor relation of the city’s voluntary hospitals, wandering indiscriminately through a series of temporary premises before finally achieving a permanent home and official recognition as a military-sponsored medical hospital in 1792. It also gained architectural extensions by both Richard and Francis Johnston and in the following decades. This new-found status and a growing re-conceptualisation of venereal disease as a legitimate medical problem rather than a matter of morality was, however, somewhat compromised by the choice of site at Townsend Street. The institution occupied a hidden part of city, appropriating the vacated home of the Hospital for Incurables, another marginalised group whose presence in the city had been viewed through the lens of superstition and fear. For the rest of its existence, the lock hospital would share this experience occupying a nebulous position between medicine and morality; disease and sin.

Using what’s left of the hospital’s records and a series of original architectural drawings, this paper discusses the presence and role of the lock hospital in the city in the eighteenth and early nineteenth century, tracking how changes in its administration and architectural form reflected wider attitudes towards disease, sexuality and gender in Georgian Dublin.

Personalised and Precision Medicine in Cancer Clinical Trials: Panacea for Progress or Pandora's Box?

Cancer clinical trials have been one of the key foundations for significant advances in oncology. However, there is a clear recognition within the academic, care delivery and pharmaceutical/biotech communities that our current model of clinical trial discovery and development is no longer fit for purpose. Delivering transformative cancer care should increasingly be our mantra, rather than maintaining the status quo of, at best, the often miniscule incremental benefits that are observed with many current clinical trials. As we enter the era of precision medicine for personalised cancer care (precision and personalised medicine), it is important that we capture and utilise our greater understanding of the biology of disease to drive innovative approaches in clinical trial design and implementation that can lead to a step change in cancer care delivery. A number of advances have been practice changing (e.g. imatinib mesylate in chronic myeloid leukaemia, Herceptin in erb-B2-positive breast cancer), and increasingly we are seeing the promise of a number of newer approaches, particularly in diseases like lung cancer and melanoma. Targeting immune checkpoints has recently yielded some highly promising results. New algorithms that maximise the effectiveness of clinical trials, through for example a multi-stage, multi-arm type design are increasingly gaining traction. However, our enthusiasm for the undoubted advances that have been achieved are being tempered by a realisation that these new approaches may have significant cost implications. This article will address these competing issues, mainly from a European perspective, highlight the problems and challenges to healthcare systems and suggest potential solutions that will ensure that the cost/value rubicon is addressed in a way that allows stakeholders to work together to deliver optimal cost-effective cancer care, the benefits of which can be transferred directly to our patients.

Spectacle design preferences among Chinese primary and secondary students and their parents: A qualitative and quantitative study

Purpose: To identify the specific characteristics making glasses designs, particularly those compatible with adjustable glasses, more or less appealing to Chinese children and their parents. Patients and Methods: Primary and secondary school children from urban and rural China with < = -1.00 diopters of bilateral myopia and their parents ranked four conventional-style frames identified by local optical shops as popular versus four child-specific frames compatible with adjustable spectacles. Scores based on the proportion of maximum possible ranking were computed for each style. Selected children and their parents also participated in Focus Groups (FGs) discussing spectacle design preference. Recordings were transcribed and coded by two independents reviewers using NVivo software. Results: Among 136 urban primary school children (age range 9-11 years), 290 rural secondary school children (11-17 years) and 16 parents, all adjustable-style frames (scores on 0-100 scale 25.7-62.4) were ranked behind all conventional frames (63.0-87.5). For eight FGs including 12 primary children, 26 secondary children and 16 parents, average kappa values for NVivo coding were 0.81 (students) and 0.70 (parents). All groups agreed that the key changes to make adjustable designs more attractive were altering the round lenses to rectangular or oval shapes and adding curved earpieces for more stable wear. The thick frames of the adjustable designs were considered stylish, and children indicated they would wear them if the lens shape were modified. Conclusions: Current adjustable lens designs are unattractive to Chinese children and their parents, though this study identified specific modifications which would make them more appealing.

Drug therapies in severe asthma - the era of stratified medicine

Difficult-to-treat asthma affects up to 20% of patients with asthma and is associated with significant healthcare cost. It is an umbrella term that defines a heterogeneous clinical problem including incorrect diagnosis, comorbid conditions and treatment non-adherence; when these are effectively addressed, good symptom control is frequently achieved. However, in 3–5% of adults with difficult-to-treat asthma, the problem is severe disease that is unresponsive to currently available treatments. Current treatment guidelines advise the ‘stepwise’ increase of corticosteroids, but it is now recognised that many aspects of asthma are not corticosteroid responsive, and that this ‘one size fits all’ approach does not deliver clinical benefit in many patients and can also lead to side effects. The future of management of severe asthma will involve optimisation with currently available treatments, particularly corticosteroids, including addressing non-adherence and defining an ‘optimised’ corticosteroid dose, allied with the use of ‘add-on’ target-specific novel treatments. This review examines the current status of novel treatments and research efforts to identify novel targets in the era of stratified medicines in severe asthma.