Skip to main content Accessibility help
×
  1. Home
  2. Publications
  3. Publishing partners
  4. Wits University Press
  5. Content Listing

Refine listing

Refine listing

Access:
Content type:
Publication date:
Apply   From and To filters
Subject: Show more
Journals Show more
Publishers: Show more
Societies Show more
Series: Show more
Collections: Show more

Actions for selected content:

Select all | Deselect all
  • View selected items
  • Export citations
  • Download PDF (zip)
  • Save to Kindle
  • Save to Dropbox
  • Save to Google Drive

Save Search

You can save your searches here and later view and run them again in "My saved searches".

Please provide a title, maximum of 40 characters.
Cancel
×

5398 results in Wits University Press

Page 241 of 270

  • Chapter 2 - Digital Concepts in Molecular Medicine

  • from Section 1 - Principles Of Cellular And Molecular Biology
    • By Barry V Mendelow, MB BCh, PhD, FCPath (Haematology), MASSAf, FRSSAf, Emeritus Professor, University of the Witwatersrand and National Health Laboratory Service, was formerly the founding Professor and Head of the Division of Molecular Medicine and Haematology at the School of Pathology and Executive Director (Research) for the University of the Witwatersrand.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 15-18

  • Summary

    INTRODUCTION

    Arguably the most important conceptual foundation of modern biology is that genetic information is essentially digital in nature. As it happens, the information technology organisational paradigm, built as it is on the special semiconductor properties of silicon, is a convenient framework for a modern understanding of cell and molecular biology and biotechnology, based as they are on the special properties of carbon, and vice versa. Just as a strategic understanding of the basis of information and communication techno - logy (ICT) is becoming an essential life skill in modern society, so a strategic understanding of the conceptual basis of molecular medicine is becoming an essential life skill for virtually all medical practitioners. The analogy of computer viruses, which traces its origins to the 1970s, introduced a useful model for the understanding of both information technology in the language of biology and molecular biology in the language of information technology. The ICT analogy is also a useful conceptual framework for the understanding of disease in a wider setting, because many noninfectious diseases are also ultimately caused or driven by inherited or acquired abnormalities in sequences of digital information. Increasingly, practical use is being made of this concept in the diagnostic process, by applying a small set of tools to identify such disease-causing digital sequences across a wide variety of diseases, whether infectious or otherwise.

    Multicellular organisms are each clones of a single cell, of which the genome, normal or abnormal, is effectively the digitally encoded design blueprint for the whole organism. The genome of any organism, be it a micro-organism, plant or animal, is the sequence of the fundamental digital units of information that constitute the specification for the construction and function, or in the case of inherited disease, dysfunction, of that organism. Disease caused by infectious microorganisms can be diagnosed by demonstrating digital sequences that define the presence of those organisms in a highly specific way that not only demonstrates the unambiguous presence of particular organisms, such as HIV, but also often contains the additional information that specifies drug resistance, virulence, etc.

  • Chapter 13 - Population Genetics

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Anthony B Lane, PhD, heads the Serogenetics Laboratory in the Division of Human Genetics, National Health Laboratory Service and School of Pathology, University of the Witwatersrand., Himla Soodyall, PhD (Human Genetics) is a medical scientist at the National Health Laboratory Service and has a joint appointment as Associate Professor in the Division of Human Genetics at the University of the Witwatersrand.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 167-176

  • Summary

    INTRODUCTION

    Mendel's investigation of heredity and the major interest in heredity in the nineteenth century arose from two related problems: how to breed improved crops and domestic animals, and how to understand the nature and origin of species. What these problems have in common is that they are concerned with populations rather than individuals. Most population concepts involve a hierarchical classification in which units are defined in terms of the extent to which individuals can be identified by common characteristics. The definition of a population for demographic purposes can be made entirely on arbitrary grounds. It can involve social, ecological or genetic criteria.

    Population genetics is the study of allele and genotype frequency distribution and change under the influence of four main evolutionary forces: mutation, genetic drift, gene flow and natural selection. These forces can result in different allele frequencies in different populations and one of the forces can dominate at one time in the evolution of a population, while others can have a major effect at another. For example, endemic exposure to pathogenic infectious organisms would select individuals with increased survival potential (determined by their phenotype, which in turn is partly determined by their genotype) and lead to an increase in the frequency of advantageous alleles during the time that the selective pressure is active. A population must be defined before an allele frequency within it can be determined.

    Human populations are made up of the old, the middle-aged and the young, those who have reproduced and those who have not. Each mature member of a population has some chance of reproducing with any other mature individual in the population. The magnitude of that chance depends on factors such as proximity, sub-culture, age, physical attributes, education and socio-economic status. The fraction of a generation that produces the next generation is called the effective population (Ne), even though non-breeding individuals certainly play important supporting roles.

    GENETIC VARIATION

    It is obvious that all individuals of the same gender in any human population are not the same; they do not look the same or react in the same way. These differences are due to their life stage, the environment in which they have developed and their genetic make-up.

  • Chapter 19 - Mammalian DNA Repair

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Alexio Capovilla, BSc (Hons), PhD, PDM, is a lecturer in the Division of Molecular Medicine and Haematology, University of the Witwatersrand, and is also employed as a senior research scientist by Elevation Biotech, a spin-out biotech company attached to the Division.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 227-237

  • Summary

    INTRODUCTION

    This chapter provides a basic description of the major biochemical pathways that operate in mammalian cells to maintain the structure and integrity of genomic DNA. This is no trivial task for multicellular organisms, since, as we shall see, they are continually exposed to a plethora of agents that cause DNA damage. Failure to repair damaged DNA efficiently and consistently is incompatible with cellular life as we know it, and a large number of severe clinical disorders can now be attributed to defects in the cellular DNA repair machinery. We will look at examples of these in a little more detail below.

    The importance of this vital function is further illustrated by the fact that DNA repair mechanisms are, for the large part, functionally conserved from primitive prokaryotes through to higher-order eukaryotes such as humans. Furthermore, at the time of writing (2006), over 150 gene products had been identified in humans that appear to have evolved primarily as either structural or catalytic components of DNA repair pathways, or gatekeepers of various stages of the cell cycle that are deliberately manipulated when DNA repair pathways are invoked. Readers are encouraged to consult an interesting web resource that has been constructed to describe the growing list of DNA repair genes at www.cgal.icnet.uk/ DNA_Repair_Genes.html

    THE SPECTRUM OF DNA DAMAGE

    For many years molecular biologists described DNA as a highly stable component of the cellular machinery that changes very little in structure or chemistry over time. The well established fact that DNA is the repository of coding information for all cellular life, and is responsible for the inheritance of this information from generation to generation, suggested that inherent physicochemical properties of DNA rendered it essentially chemically immutable. Recent evidence, however, has revealed a vastly different scenario, one in which all organisms are constantly exposed to a plethora of agents that cause significant structural and chemical changes in their DNA. Moreover, these changes are now known to occur through ongoing inter actions between DNA and by-products of normal cellular metabolism.

  • Keynote Essay 6: Molecular Research Case Study: Developing Novel RNA Interference-based Therapy

  • from SECTION 3 - MOLECULAR THERAPEUTICS
    • By Patrick Arbuthnot, MB BCh, BSc (Hons), PhD, is a reader in the Division of Molecular Medicine and Haematology at the Medical School of the University of the Witwatersrand, Johannesburg. He has a research interest in using nucleic acid transfer to develop new approaches to treating viral infections of South African importance., Marc S Weinberg, PhD, is a senior lecturer in the Division of Molecular Medicine and Haematology, University of the Witwatersrand, and a member of the Antiviral Gene Therapy Research Unit.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 441-448

  • Summary

    THE VALUE OF ACADEMIC RESEARCH

    Research can be defined as the process of discovery and creation of new knowledge. A vital role for universities is to carry out research, and success in this activity is a good gauge of the well-being of these academic institutions. All leading universities of the world (such as Harvard, Cambridge and Oxford universities) have a strong commitment to supporting research, and this is the foundation of their good reputations. Research is vital to any society and positive outcomes go way beyond the direct practical application of new discoveries. By nurturing creativity, critical thinking, open-mindedness and enquiry, research has the broad benefits of building a strong democratic ethic in society. Today we refer to the importance of the ‘knowledge based economy’ where societies become more reliant on creation and exploitation of new knowledge to understand and overcome economic and political challenges. An active research community allows countries to benefit directly from new developments of the twenty first century and to participate in developing a knowledge-based economy. The benefits of an active research environment can have both direct and indirect effects on society. Some of these benefits are listed below.

  • • Improved training of students. An often under-appreciated role of research is that it is beneficial to teaching in universities. By and large, research activities are supportive of university educational programmes, and teachers who are immersed in active research generally make better instructors. Research leads to more meaningful insight into a subject, and educators pass this benefit on to students through better teaching. High-level training of students that is not based on a foundation of academic research risks becoming stale and outmoded.

  • • Promoting innovation for patient care. Insights gained from research on medical challenges contribute significantly to understanding and overcoming patient problems, which collectively makes for better patient management and care.

  • • Broadening the knowledge base for the good of humanity. Some of the most significant breakthroughs in technology have come from unlikely research contributions. Research does not always produce immediately obvious practical benefits, and it is often only after several years that the utility of research becomes apparent.

  • Chapter 41 - Bioinformatics and Molecular Medicine

  • from SECTION 4 - RESEARCH AND THE CONTINUING EVOLUTION OF MOLECULAR MEDICINE
    • By Andries J Oelofse, BSc, BSc (Hons), MSc (Bioinformatics), held the position of Bioinformatics Consultant at Wits Bioinformatics, a node of the National Bioinformatics Network, at the time of writing. He has a keen interest in the contribution of bioinformatics to molecular medicine., Michèle Ramsay, PhD (Human Genetics), is currently Professor and Head of the Molecular Genetics Laboratory, Division of Human Genetics, National Health Laboratory Service and University of the Witwatersrand.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 456-466

  • Summary

    INTRODUCTION

    To study life at the molecular level, various types of data must be in a ‘human readable format’. There are many tools and techniques with which we can determine the sequences of the nucleic acids and proteins that allow us to draw parallels between what we physically observe and what is happening at the molecular level. The amount of data these tools generate is vast. The data can amount to several gigabytes per experiment, and all must be correctly stored and interpreted in order to be useful. There are also several related types of information that assist in the better understanding of the function of genes and proteins in the organism.

    Bioinformatics is the discipline that deals with the problem of massive data sets with diverse data in molecular research. It concerns the storage, visualisation, manipulation, analysis and integration of biological information using computers. Initially, the biological information that was required to be managed by bioinformaticists was the nucleotide and amino acid data derived from DNA and protein sequencing, but today with new technologies and approaches there are many more diverse data types that must be managed.

    A paradigm shift is starting to occur in molecular research. The emphasis on hypo - thesis-driven research is declining, and is shifting towards exploratory observations. These observations are typically done in a very high-throughput way, meaning that in some cases literally billions of data points are considered per experiment over a relatively short period of time. This would be impossible if all the observations had to be made by human observers, and computers are extremely important for data capturing, management and analysis in experiments of this type.

    A very good example of technology that requires computers for data capture, management and analysis is microarray technology. This technology enables the determination of miRNA expression levels for all genes in a sample at a given time point. It is utilised by com paring the gene expression levels between a test and a reference sample, and then identifying the genes that are up-regulated in terms of their expression as well as those that are down-regulated. These genes are very interesting to examine, since (usually in combination) they determine how the phenotype of a test sample would differ from the reference sample.

  • Keynote Essay 4: Microbes, Molecules, Maladies and Man

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Adriano G Duse, MB BCh (University of the Witwatersrand), DTMH, MMed (Microbiology), FCPathSA (Microbiology), is currently Professor and Head of the Division of Clinical Microbiology and Infectious Diseases of the School of Pathology, National Health Laboratory Service and the University of the Witwatersrand, Johannesburg.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 277-283

  • Summary

    INTRODUCTION

    The planet Earth was formed, in a molten state, some 4.5 billion years ago. It cooled off sufficiently 4 billion years ago to allow the formation of the oceans. Cyanobacteria, found in rock fossil records that are approximately 3.6 billion years old, provide the earliest evidence of life in the form of complex unicellular organisms. Molecular phylogeny is the tool that enables us to understand life in all its complexity and recognise relations hips between organisms. In essence, using molecular techniques we are able to deter mine the evolutionary relationships of living creatures. By comparing the difference in sequences of homologous genes encoding ribosomal RNA (16S rRNA genes from prokaryotic cells and 18S rRNA from eukaryotic cells) we can measure the evolutionary distance between species of organisms. Computer analysis of rRNA gene sequences suggests that cellular life has evolved along three major lineages. Two of these, Bacteria and Archaea, are exclusively microbial and consist of prokaryotic cells. The third lineage, Eukarya, not only contains unicellular organisms but also myriads of multicellular organisms. Two important points have emerged from the study of molecular phylogeny: 1) unicellular organisms are the major and most diverse form of life, and 2) eukaryotes are not of recent origin, as previously thought, but as ancient as the Bacteria and Archaea lineages, all of which have emerged from a universal ancestor. Although the human race may live in harmony, and is subject to colonisation with many different prokaryotic (e.g. bacteria) and eukaryotic (e.g. fungi and parasites) organisms, this harmony is shattered from time to time when a relatively restricted number of microbial species enter our body and cause pathology – infection.

    Antimicrobials, developed on a mass scale from the 1940s onwards, brought renewed hope that, to quote the UN Surgeon General in his address to Congress in 1969, ‘We can close the book on infectious diseases’. Unfortunately, nothing could have been further from the truth. With the continuous emergence of microbes that display a vast array of antimicrobial resistance mechanisms, the ‘golden era’ of antimicrobials is under serious threat.

  • Chapter 40 - Approaches to Research in Molecular Medicine

  • from SECTION 4 - RESEARCH AND THE CONTINUING EVOLUTION OF MOLECULAR MEDICINE
    • By Michèle Ramsay, PhD (Human Genetics), is currently Professor and Head of the Molecular Genetics Laboratory, Division of Human Genetics, National Health Laboratory Service and University of the Witwatersrand.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 451-455

  • Summary

    The knowledge presented in this book is the result of meticulous, extensive, well thought out and often very costly research. Much of this research is based on the seminal works of early pioneers in the fields of biochemistry, genetics and statistics. The modern era of molecular medicine perhaps began with the deciphering of the code of life, the structure and function of the DNA molecule, and an understanding of how it codes for the proteins that make up cells and ultimately living organisms. What were considered beautifully simple mechanisms are now, however, being understood to be increasingly more complex. Biological systems are by nature extremely intricate and subject to fluctuating information inputs and functional outputs. Consider, for example, the expression of a specific gene. This gene may be switched on only during a specific developmental stage, and depending on the position of the cell in the developing organism and its exposure to a concentration gradient of a critical factor, its expression will be attenuated to ensure appropriate synthesis in that position in the body. To understand the detailed workings of living cells requires research.

    Research is a process aimed at systematically gathering information that can be interpreted to gain knowledge related to a specific question or to support or refute a hypo thesis. A stepwise process, following ethical rules and regulations, has to be followed to obtain valid results and their interpretation has to be subjected to peer scrutiny (Table 1). There are variations on the theme depending on the nature of the research, which may range from basic research to clinically orientated research. The latter particularly needs to consider the rights and protection of the subjects involved with the research.

    THE PROCESS OF RESEARCH

    All research, irrespective of the size or complexity of the research project, needs to be preceded by an extensive literature review and a thorough understanding of the subject matter. It is not possible to formulate a relevant research question without in-depth know ledge of what is already known on the topic and an understanding of where key information is still lacking on a particular aspect of the molecular basis of disease.

  • Chapter 20 - Tumour Suppressor Genes and Inherited Susceptibility to Cancer

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Kate Hammond, BSc (Hons), MT, PhD, is Professor of Molecular Medicine and Haematology, University of the Witwatersrand.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 238-248

  • Summary

    INTRODUCTION

    The discovery of proto-oncogenes, which function as promoters of cellular proliferation, was a highlight in molecular medicine, providing insight into the mechanisms regulating growth control and leading to the idea that a distinct group of ‘anti-oncogenes’ may oppose their effects. This proved to be the case and over the past 20 years many such genes, known as tumour suppressor genes, have been identified. Proto-oncogenes are genes that encode proteins which activate proliferation and survival in normal cells; these proteins include growth factors, receptors, signal transduction proteins, transcription factors, positive cell-cycle regulatory proteins and cell survival factors. Tumour suppressor genes, on the other hand, encode proteins that normally suppress cell proliferation and promote cell death; they slow down cell division, activate apoptosis and repair DNA. The actions of proteins encoded by proto-oncogenes and tumour suppressor genes are finely coordinated to maintain a dynamic balance between growth stimulation and inhibition. When this balance is disrupted cells may become cancerous. Mutations of proto-oncogenes, which increase their activity, may con - tribute to cancer, whereas tumour development is associated with the inactivation of tumour suppressor gene function.

    Mutation of a single copy of a protooncogene can have a dominant growth promoting effect on a cell. The oncogene can therefore be detected by its effect when it is added, by DNA transfection or through infection with a viral vector, to the genome of a suitable type of cell. In contrast, both copies of the normal tumour suppressor gene must be removed or inactivated in the diploid somatic cell before an effect is seen – the cancer-causing mutations are recessive (see Figure 1). This calls for a different approach to discover what is missing – one cannot, for instance, use a cell transformation assay to identify something that is simply not there.

    The existence of tumour suppressor genes was demonstrated by showing that somatic cell hybrids, created in vitro by fusing a cancer cell with a non-cancerous one, most often took on the characteristics of the cancer-free parent. The identification of specific genes, however, was initially the result of studies of inherited cancers, such as hereditary retinoblastoma and Wilms’ tumour.

  • Chapter 18 - Oncogenes

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Natalie A Whalley, PhD, lectures in the Division of Molecular Medicine and Haematology, School of Pathology, University of the Witwatersrand., Kate Hammond, BSc (Hons), MT, PhD, is Professor of Molecular Medicine and Haematology, University of the Witwatersrand.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 218-226

  • Summary

    INTRODUCTION

    The cell is a complex array of networks – a protein communication system, with phosphorylation cascades transmitting messages from receptors at the surface to the nucleus. Individual proteins integrate signals from a diversity of activator molecules, transducing them through intracellular signalling pathways to various target or effector proteins. Circuits of this nature enable a cell to respond to external factors and to modify its own function. In particular, in this chapter we will look at the way in which growth factors and hormones regulate the processes of cell division and differentiation, and cell survival.

    Proto-oncogenes have been identified as genes encoding protein members of cascades dedicated to the transmission of signals regulating growth and survival. The actions of proto-oncogene-encoded proteins are tightly controlled under normal circum stances. If such proteins are abnormal, or if there is too much of them, signals are deregulated, downstream transducing molecules are activated and there is excessive stimulation of cell growth and survival. When intracellular signal pathways are out of control, a cell may begin to multiply unceasingly in a way that can lead to cancer.

    We define a proto-oncogene as the form the gene takes as it carries out its usual functions within a cell – it has the potential to become an oncogene. Proto-oncogenes may also be referred to as cellular oncogenes (conc). An oncogene is a mutated form of a proto-oncogene producing a protein, which stimulates uncontrolled growth and promotes cell survival. The homologous counterparts of certain oncogenes occur in retroviruses; these are viral oncogenes (v-onc). Oncogenes are dominant in the sense that only one allele needs to be mutated to cause cancer.

    Many of the human oncogenes were discovered through the study of animal retro - viruses, acutely transforming RNA tumour viruses, whose genomes are reverse transcribed into DNA in infected cells. During the course of infection, retroviral DNA is inserted into the chromosomes of host cells. The retro viral oncogenes are derived from the normal cellular genes of the host which have been incorporated into the retroviral genome. In 1970, the first oncogene, now known as the SRC oncogene, was identified in a chicken tumour virus.

  • Chapter 22 - Leukaemias and Lymphomas

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Tracey M Wiggill, MB BCh, MMed (Haematology), works as a senior haematopathologist in the Division of Molecular Medicine and Haematology, National Health Laboratory Service and University of the Witwatersrand. She runs the diagnostic immunophenotyping unit at Johannesburg Hospital and her research interests include the molecular diagnostics of haematological malignancies., Nicole S Holland, MB BCh, FCPath (Haematology) is currently employed at the Johannesburg Hospital by the NHLS and is a consultant haematologist in the Division of Molecular Medicine and Haematology at the University of the Witwatersrand., Pascale Willem, qualified as a medical doctor in Paris and specialised in human genetics (Grenobles- Marseille, France). Since 1990 she has run the Somatic Cell Genetics Unit in the Division of Molecular Medicine and Haematology, University of the Witwatersrand. She is involved in cancer research and diagnostics using both molecular genetics and cytogenetics techniques., Lindsay Earlam, MB BCh, FCPath (SA) (Haematology) is currently practising as a consultant haematologist with Lancet Laboratories. Interests include leukaemia/lymphoma immunophenotyping, the molecular pathogenesis of leukaemia and haematological disease in the South African context.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 261-270

  • Summary

    INTRODUCTION

    Cells within a multicellular organism are genetically encoded to function in the best interests of the organism as a whole. As such, each cell receives signals from its own cytoplasm and nucleus (such as those provided by the cell cycle machinery) and from outside the cell (such as those provided by cytokines and growth factors). These signals are integrated within the cell to give a cohesive picture of what is required by the organism as a whole. Each cell uses this information to commit to one of three options, namely entry into the cell cycle and proliferation (cell division to create identical daughter cells), cell differentiation (acquisition by the cell of its more specialised functions), or apoptosis (program - med cell death).

    A malignancy may arise when any one of these processes escapes its normal control mechanisms, leading to uncontrolled expansion or persistence of an abnormal clone of cells. Malignancies therefore arise by one of three major mechanisms:

  • • Excessive proliferation of cells

  • • Failure of cells to differentiate normally

  • • Failure of cells to undergo normal cell death (apoptosis).

    • Although one mechanism usually predominates in haematological malignancies, often the other mechanisms contribute to oncogenesis. By definition, a malignancy is monoclonal (i.e. arises from a single abnormal cell), with any abnormalities in the genome being passed from parent to daughter cell. Additional mutations may be acquired by the daughter cells leading to a progressive increase in aggressiveness of the malignancy.

    To recapitulate from the previous chapters, two major groups of genes have been shown to play a role in malignancy, namely the oncogenes and the tumour suppressor genes. Proto-oncogenes (normal cellular counterparts of oncogenes) are commonly the cell cycle stimulatory proteins (such as growth factors, growth factor receptors or downstream stimulatory molecules). These molecules cause malignancy through gain of function mutations. Tumour suppressor genes are the cell cycle brakes (or control proteins) and are active at the cell cycle checkpoints. The loss of tumour suppressor function is associated with malignant change.

    BASIC PATHOLOGY OF THE LEUKAEMIAS AND LYMPHOMAS

    The leukaemias are a broad group of malignancies of cells of haemopoietic lineage, which involve the bone marrow and the peripheral blood.

  • Chapter 32 - Targets for Molecular Therapy: The Biology of Haemostasis

  • from SECTION 3 - MOLECULAR THERAPEUTICS
    • By Marion Münster, BSc (Med), MB BCh, DTMH, MMed (Haematology), is Pathologist in Charge, Coagulation Laboratory, Division of Molecular Medicine and Haematology, National Health Laboratory Service and University of the Witwatersrand., Nanthakumarn Chetty, BSc, BSc (Hons), MSc, PhD, Associate Professor, University of the Witwatersrand and National Health Laboratory Service, heads the Platelet Research Unit in the Division of Molecular Medicine and Haematology, School of Pathology, at the University of the Witwatersrand.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 383-390

  • Summary

    INTRODUCTION

    Some of the early candidate molecules identified as having potential therapeutic value included proteins involved in the promotion or inhibition of the normal clotting mechanisms, for use in inherited or acquired bleeding or clotting disorders, respectively. In order to understand the rational use of such molecules, which could be produced as recombinant proteins or incorporated into gene therapy strategies, it is necessary to have a thorough understanding of the molecular and cellular mechanisms of the normal physiological haemostatic (‘stopping of bleeding’) process. The primary principle of haemostasis is to minimise blood loss at sites of vessel injury by forming a thrombus (clot) and at the same time maintaining blood flow (Figure 1). In order to achieve this there is a highly regulated, fine-tuned interaction of multiple processes, involving the blood vessel wall, principally the endothelium, plate lets and noncellular blood constituents.

    The core elements of haemostasis include vasoconstriction, platelet activation, the pro cess of coagulation and fibrinolysis (clot break - down). All of these processes are initiated simultaneously, triggered by a breach in blood vessel integrity. Endothelial cell damage results in exposure of collagen, which triggers platelet adhesion and activation, while tissue factor expression activates the coagulation cascade resulting in the formation of a fibrin meshwork.

    Platelet adhesion and activation is conventionally known as ‘primary haemostasis’ and the process of coagulation and fibrin formation as ‘secondary haemostasis’. In simplistic terms, the platelet plug can be considered to be the ‘bricks’ and the fibrin meshwork the ‘cement’, both being required for the formation of a stable thrombus.

    PLATELET ADHESION AND ACTIVATION

    Platelets play a critical role in the normal physiology of haemostasis. At sites of endothelial cell injury, platelets adhere to a variety of subendothelial matrix structures via a multitude of platelet surface receptors.

  • Chapter 42 - Personalised Medicine: Dream or Reality?

  • from SECTION 4 - RESEARCH AND THE CONTINUING EVOLUTION OF MOLECULAR MEDICINE
    • By Wendy Stevens, MB BCh, MMed (Haematology), FCPath (Haematology), is Head of the Division of Molecular Medicine and Haematology, University of the Witwatersrand and National Health Laboratory Service. Professor Stevens has more than 15 years’ haematology and routine molecular testing laboratory experience and is principal investigator on a number of internationally grant-funded projects.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 467-470

  • Summary

    Imagine a scenario in which you could predict your likelihood of getting a disease, accurately determine the unique biological characteristics of that disease process, suggest appropriate rationally designed therapy, and predict adverse effects of proposed treatment. Many of the chapters in this textbook provide evidence to suggest that this is more than a promise and fast becoming a reality. Progress towards these lofty goals has been aided recently by remarkable scientific achievements such as: 1) the completion of the human genome project and the realisation that genetic variation plays a significant role in deter mining susceptibility to disease and the likely response to its management; 2) understanding the important contribution made by epigenetics, with mediators such as methylation and histone modification, to disease processes; and 3) the discovery of microRNAs and their importance in normal physiology and disease. These factors together with the significant advances in the development of high-through put laboratory technologies have rapidly generated a host of new predictive sciences that includes genomics, proteomics and metabolomics among others.

    These developments have resulted in the clinical laboratory and the pathologist taking an increasingly prominent role in the development of assays able to stratify patients into appropriate risk and treatment groups. In tandem with advances in laboratory techno - logy, a significant investment in bioinformatics and the development of sophisticated IT systems will be needed to facilitate translation of data into clinically meaningful algorithms. Remarkable advances have also been made in the field of radiology with molecular imaging techniques that use targeted drugs and have been useful for patient selection and monitoring response to treatment, furthering the personalised medicine approach.

    Significant progress has been made in the biological characterisation of disease with technologies such as microarray technology leading the way, using either genome-wide RNA expression profiling or large-scale single nucleotide polymorphism (SNP) analysis using comparative genomic hybridisation (CGH) arrays or a combination of these methodologies. These techniques have been used to improve understanding of the underlying pathogenesis of a disease with the ability to differentiate distinct biological groups for the identification of either rational or novel treatment approaches. Many of these approaches have originally been evaluated in the oncology fields, where 1) the likelihood of mortality is high, 2) drugs are expensive and have a narrow therapeutic index, and 3) toxicities are common.

  • Chapter 28 - Malaria

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Theresa L Coetzer, PhD, Associate Professor and Principal Research Scientist, heads the Red Cell Membrane Research Unit and the Plasmodium Molecular Biology Research Unit in the Division of Molecular Medicine and Haematology, School of Pathology, University of the Witwatersrand and National Health Laboratory Service. She is a founder member of the South African Malaria Initiative.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 339-349

  • Chapter 14 - Complex Multifactorial Inheritance

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Zané Lombard, MSc (Biochemistry), is a medical scientist in the Division of Human Genetics, University of the Witwatersrand and National Health Laboratory Service.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 177-186

  • Summary

    INTRODUCTION

    Many disorders with a Mendelian pattern of inheritance have been well characterised and many of the genes controlling these disorders have been identified. There are, however, many common diseases with an inherited component that do not follow a specific pattern of inheritance. These diseases are conventionally known as complex multi factorial traits and include conditions such as asthma, diabetes and many of the cardio vascular disorders. The term multifactorial indicates that there are multiple causative agents – both genetic and environmental. These traits therefore have a complex molecular mechanism that involves many processes such as physiological mechanisms, development and homeostasis, to name but a few.

    This chapter will review basic concepts of multifactorial inheritance and illustrate what a complex disease is, and how it differs from Mendelian disorders. Furthermore, the design and implementation of complex disease gene discovery, and the strengths and pitfalls of these approaches, will be discussed. Finally, the impact of the knowledge of complex disease genetics on clinical medicine and its relevance to future disease treatment will be discussed.

    HOW DO COMPLEX DISEASES DIFFER FROM MENDELIAN DISORDERS?

    Complex diseases differ in very distinct ways from Mendelian disorders, and the key differences are summarised in Table 1. The single most important difference is related to the impact of the genetic factors on the disease. For most Mendelian diseases, the inheritance of a pathogenic gene variant or mutation is associated with that disease because it has such a debilitating impact on the gene product that it almost always results in disease. This is not the case with complex diseases, where the presence of a specific genetic factor is not causal but may increase or decrease the risk of developing disease. Risk is defined as the probability of an adverse event and its value in clinical medicine is primarily to predict outcome. The goal of complex disease prediction is therefore to identify an individual or a population in which an intervention could prevent adverse outcome. Complex diseases are usually not influenced by only one gene but by many genes that contribute to disease outcome and may have an additive, multiplicative or interactive effect.

  • Chapter 31 - Vaccines and Immunisation

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Maria A Papathanasopoulos, PhD, is a senior lecturer in the Division of Molecular Medicine and Haematology, University of the Witwatersrand, and co-head of the HIV Pathogenesis Research Laboratory.
  • Edited by Barry Mendelow, University of the Witwatersrand, Johannesburg, Michèle Ramsay, University of the Witwatersrand, Johannesburg, Nanthakumarn Chetty, University of the Witwatersrand, Johannesburg, Wendy Stevens, University of the Witwatersrand, Johannesburg
  • Book:
    Molecular Medicine for Clinicians
    Published by:
    Wits University Press
    Published online:
    04 June 2019
    Print publication:
    01 October 2008, pp 367-376

  • Summary

    INTRODUCTION

    Infectious diseases account for approximately 25% of global mortality, and kill at least 15 million people per year. Of those who die at least five million are children younger than 5 years of age. The burden of infectious diseases can be greatly reduced if we vaccinate all populations at high risk of disease and ensure that all children have access to basic vaccines regardless of their geographical location or economic status.

    Immunisation or vaccination is the most cost-effective form of public health intervention in the protection of children, families and communities against infectious diseases. Worldwide immunisation, as well as improvements in hygiene and sanitation, have revolutionised child health and improved the quality of life of adults. Immunisation prevents millions of deaths every year, and reduces the risk of disability caused by infectious disease. In spite of these successes, however, almost two million children die every year from diseases against which effective vaccines are available at low cost.

    By immunising specific population groups, for example children, serious infectious diseases and their complications can be prevented, contained and eliminated, a process referred to as herd immunity. The art of vaccination involves the production of antigenic preparations from the pathogen that are safe to administer, induce the right sort of immunity for prevention or treatment of disease, and are affordable to the population at which they are aimed.

    This chapter describes the currently avail - able categories of vaccines. All health professionals have a duty to be properly trained in all aspects of immunisations and a responsibility to fully support the national childhood immunisation programmes based on the available scientific evidence.

    VACCINES: A HISTORICAL PERSPECTIVE

    Smallpox is a highly infectious, devastating and disfiguring disease that is caused by variola or smallpox virus, a member of the Orthopoxviridae. The disease is characterised by the presence of numerous pustules all over the body which contain infectious virus. The fatality rate is over 25% for patients infected by Variola major, while smallpox caused by V. minor has a much lower fatality rate (less than 5%).

Page 241 of 270