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4968 results in Wits University Press

Page 219 of 249

  • 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%).

  • Chapter 21 - Carcinoma

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Alan C Paterson, MB BCh, PhD, FCPath (SA), is Professor and Head, Division of Anatomical Pathology in the School of Pathology of the National Health Laboratory Service and University of the Witwatersrand., Leandra Cronjé, BSc, MSc, PhD, is a research fellow in the Division of Anatomical Pathology, School of Pathology, 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 249-260

  • Summary

    INTRODUCTION

    Carcinoma is defined as a malignant tumour of epithelial tissue. A variety of types are recognised, reflecting the tissue of origin. Broadly, malignant tumours of squamous epithelial origin, or squamous carcinomas, are differentiated from the tumours of glandular epithelia – the adenocarcinomas. Carcinomas constitute the most prevalent human malignancy, accounting for approximately 85% of tumours worldwide.

    AETIOLOGY AND PATHOGENESIS

    Certain crucial concepts have long been identified that, in part, serve to explain the pathogenetic mechanisms of this group of tumours. Firstly, carcinomas are a phenomenon associated with ageing. They are uncommon before 50 years, but thereafter increase exponentially with increasing age. Furthermore, there are often distinct geographical trends associated with carcinomas of different organ systems. It was therefore postulated early on that the aetiology of carcinoma has its origin in the environment. This is now largely established. General aspects of the pathogenesis of carcinomas have been covered in Chapter 17. There are a number of additional factors of special relevance to carcinomas. These include:

  • • Chemicals

  • • Dietary factors

  • • Physical agents

  • • Infectious organisms.

    • Many chemicals are now identified as causing malignant disease. Probably the best example is the relationship between cigarette smoking and bronchogenic carcinoma, one of the commonest visceral malignancies worldwide. Early epidemiological studies identified a strong association between most carcinomas of the lung and chronic tobacco usage. At a histological level, the simple columnar epithelium that lines most of the respiratory tract is subjected to constant irritation by smoke inhalation and responds by changing its phenotype to that of a mature squamous epithelium, a process known as metaplasia. Thereafter a percentage of these metaplastic epithelia undergo further cytological changes with increasing abnormality in numbers, shape, size and orientation of the epithelial layer, the process of dysplasia, considered a pre-neoplastic lesion. Once a highgrade dysplasia, sometimes loosely termed carcinoma in situ, is identified, this abnormal tissue may invade across the basement membrane of the epithelium, thus progressing to invasive carcinoma.

  • Chapter 16 - Medical Genetics

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Nerine E Gregersen, MB BCh, MSc (Med), FCPaed (SA), Cert (Medical Genetics), DCH (SA), is a clinical geneticist and associate lecturer in the National Health Laboratory Service and Division of Human Genetics, School of Pathology, University of the Witwatersrand., Amanda Krause, MB BCh, PhD, is Associate Professor and Head of the Clinical Section in the Division of Human Genetics, National Health Laboratory Service and University of the Witwatersrand. She is primarily a clinician, whose research has been aimed at understanding the molecular basis of a number of genetic diseases in South Africa, which she sees as critical to providing patients with appropriate genetic tests in the local context. She has taught medical genetics at undergraduate and postgraduate level.
  • 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 194-202

  • Summary

    INTRODUCTION

    As the burden of birth defects is high in middleincome countries like South Africa, clinicians frequently have to care for patients with such conditions. This chapter aims to provide the clinician with a clear understanding of the aims and processes of medical genetics, and how individuals with birth defects should be cared for.

    When affected individuals and their families attend a genetic clinic, they usually want answers to five questions:

  • What is it?

  • What caused it?

  • What does it mean in terms of care?

  • Will it happen again?

  • Can it be prevented?

    • The care of individuals with birth defects is accomplished by providing information that answers these questions. In addition, it is necessary to provide psychosocial support while individuals and families come to terms with the information and make medical, social and reproductive decisions.

    PROVIDING INFORMATION

    Making a diagnosis: ‘What is it?’

    Making a diagnosis in a person with a birth defect is often challenging. An exact diagnosis allows for calculating accurate recurrence risks in a family, and this should be conveyed during genetic counselling. As with any medical problem, making a diagnosis depends on taking a history, doing an examination, and performing relevant investigations. Within each activity, ‘genetically’ orientated details will apply.

    History

  • • The family history should note particular aspects such as similarly affected individuals, individuals with different but linked signs and symptoms, possible patterns of inheritance, consanguinity, previous mis - carriages, stillbirths, and abnormal and/or intellectually impaired individuals.

  • • Pregnancy history should include information about age, maternal illnesses, maternal medication use in pregnancy, and pregnancy-related events that could result in birth defects such as maternal infections or teratogen exposure (for example alcohol).

  • • Birth history must be detailed and complete, and include birth parameters.

  • • Medical progress should note problems such as growth abnormalities (over growth or restricted growth), failure to thrive, seizures, cardiac or other organ dysfunction, recurrent infections and feeding difficulties. In adult-onset conditions, age of onset of symptoms is important.

  • Keynote Essay 2: The Human Genome

  • from Section 1 - Principles Of Cellular And Molecular Biology
    • 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 113-120

  • Summary

    ‘It's a history book – a narrative of the journey of our species through time. It's a shop manual, with an incredibly detailed blueprint for building every human cell. And it's a transformative textbook of medicine, with insights that will give health care providers immense new powers to treat, prevent and cure disease.’ Francis Collins, Director of the National Human Genome Research Institute (NHGRI) at the NIH

    Many believe that the human genome is the foundation of biomedicine in the twenty-first century. The 3 billion nucleotide base sequence has been described as the book of life, harbouring the ordered information for every gene that encodes the proteins that make up our cells. Information gleaned from the human genome and the genomes of pathogens will inform the future practice of molecular medicine and predisposition to disease.

    During the 1980s the techniques for DNA manipulation and investigation were becoming established and at this time it was beginning to be possible to identify DNA variation or polymorphism. This was not done with the knowledge of DNA sequences, but by cutting DNA with restriction endo nucleases. The DNA fragments that were generated were separated according to size in a gel using an electric current and finally the individual segments of DNA were singled out by using specific DNA probes or sequences of known origin. Many pages of scientific journals were devoted to recording the small successes and in order to use the information, scientists had to contact the laboratories to request a sample of the probe DNA to be sent by post. Science was more personal, requiring interaction, discussion and collaboration, and discoveries took time.

    At this time genetic maps had to be built, clone by overlapping clone, as part of the voyage of discovery. Scientists were like the sixteenth-century mariners with only the chromosomes in place of the stars to assist them in their navigation. It seemed little short of a miracle when the early successes in identifying disease-causing genes materialised.

    Among the first disease loci to be mapped to chromosomal regions, bordered by two known markers, were chronic granulomatous disease and Duchenne muscular dystrophy on the X chromosome, and the cystic fibrosis and Huntington disease loci which were mapped to chromosomes 7q31 and 4p, respectively.

  • Chapter 15 - Molecular Basis for Phenotypic Variation

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Nerine E Gregersen, MB BCh, MSc (Med), FCPaed (SA), Cert (Medical Genetics), DCH (SA), is a clinical geneticist and associate lecturer in the National Health Laboratory Service and Division of Human Genetics, School of Pathology, University of the Witwatersrand., Amanda Krause, MB BCh, PhD, is Associate Professor and Head of the Clinical Section in the Division of Human Genetics, National Health Laboratory Service and University of the Witwatersrand. She is primarily a clinician, whose research has been aimed at understanding the molecular basis of a number of genetic diseases in South Africa, which she sees as critical to providing patients with appropriate genetic tests in the local context. She has taught medical genetics at undergraduate and postgraduate level.
  • 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 187-193

  • Summary

    INTRODUCTION

    Even though we carry the same basic genetic material, we are all different. Even individuals with the same genetic disease may have very different presenting features, severity of disease, and clinical progression. What accounts for these differences? Some of our differences can be due to environmental influences, but others are caused by differences in our genes. The degree to which either genetics or the environment affects our external appearance forms the basis of the ‘nature and nurture’ debate. This chapter examines some of the reasons why individuals with the same genetic disease may differ from each other.

    A person's phenotype is their external form (physical, physiological and biochemical), which may be within or outside normal boundaries. Their genotype refers to their underlying genetic make-up. The genotypephenotype correlation refers to the degree to which the genetic component influences the final physical form, and to what extent knowledge of the genotype might predict the phenotype. Heterogeneity is a term which indicates that something is ‘different in character’ or ‘varies in content’ (Oxford English Dictionary, 9th Edition). Phenotypes and genotypes are generally heterogeneous.

    GENOTYPIC VARIATION

    Different forms of a gene (alleles) exist in Hardy-Weinberg equilibrium in large randomly mating populations. However, certain alleles become more common in certain populations because several factors disturb this Hardy-Weinberg equilibrium. These factors include non-random mating, a rapid mutation rate, selection, a small population size, migration (gene flow between populations) and random drift.

    Some of these factors may result in a disease-causing allele becoming common in a certain ethnic group, and the disease caused by this allele will then be more common in that ethnic group. It is important for medical professionals to be aware of the ethnicity of their patients for the following reasons: 1) certain diseases are more common in certain populations and therefore a high index of suspicion should be maintained in individuals with certain ethnic backgrounds, and 2) certain gene mutations are more common in certain population groups, and by providing a laboratory with information on the ethnic background of a patient, appropriate testing can be done, preventing a waste of time and money, and minimising the chance of obtaining false negative results.

  • Chapter 7b - Protein Methods

  • from Chapter 7 - Tools of Molecular Medicine
    • 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 83-94

  • Summary

    INTRODUCTION

    In the post-genomic era, with sequencing of the entire human genome complete, there has been a great increase in our knowledge regarding the function of proteins encoded by the genome, the so-called proteome, and the role that aberrant protein expression and/or function plays in human disease pathogenesis. ‘Genomics’ refers to the comprehensive study of the function, interactions and dynamics of genes. In turn, ‘transcriptomics’, while having a similar objective, describes the function, interactions and dynamics of the genomic transcripts (i.e. mRNA, tRNA, rRNA and small RNAs such as miRNA and siRNA). ‘Proteomics’, by logical succession, describes the equivalent parameters for the complete set of proteins expressed by the genome through its transcripts. The entire set of proteins expressed by a particular cell/ organ ism constitutes its proteome. A number of variations on this theme are encountered increasingly in the literature. For instance, ‘metabolomics’refers specifically to the study of genes, transcripts and proteins involved in the regulation of metabolism.

    In this chapter, we present a brief overview of some of the important tools that have been used to study the basic physicochemical properties of proteins, which have contributed significantly to developments in the field of proteomics. We also describe how these are increasingly being applied in the diagnosis and understanding of human disease.

    PROTEIN BIOCHEMISTRY: BASIC CONCEPTS

    The central dogma of molecular biology describes the process by which the genetic information contained within an organism's genes is translated into the functional components of life, proteins. This involves the produc tion of messenger RNA (mRNA) from the coding DNA sequence (transcription), which then serves as a template for protein synthesis (translation). In this manner, proteins are synthesised by polymerisation of the basic building blocks of all proteins, amino acids, in an order that is defined by the sequence of nucleotides in the coding DNA. It is the sequence in which these amino acids are incorporated into a protein molecule that is largely responsible for determining the threedimensional structure of the protein. This, in turn, is essentially what determines the biochemical activity of the protein and its role in the cell's life.

  • Chapter 17 - Neoplasia: General Considerations

  • from SECTION 2 - MOLECULAR PATHOLOGY
    • By Alan C Paterson, MB BCh, PhD, FCPath (SA), is Professor and Head, Division of Anatomical Pathology in the School of Pathology of the National Health Laboratory Service and University of the Witwatersrand., Leandra Cronjé, BSc, MSc, PhD, is a research fellow in the Division of Anatomical Pathology, School of Pathology, 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 208-217

  • Summary

    NORMAL GROWTH AND DEVELOPMENT AND NEOPLASIA (‘NEW GROWTH’)

    From the first division of the fertilised egg cell until the death of the adult human decades later, a single copy of the original diploid genome needs to be replicated countless times to allow for growth of the embryo, fetus, neonate, child, adolescent and adult (consisting of about a hundred trillion offspring from that original fertilised egg cell), and also for the maintenance of cell numbers to replenish those lost through normal use and wear and tear (for instance we replace 250 thousand million red cells every single day, which is about three million each second, and that's just the red cells!). It is truly astonishing that this is generally accomplished with the exquisite precision that we tend to take for granted, especially when we understand that theoretic ally it just takes a single mistake in the copying of a single base, if that base is critically located in a growth-controlling gene, in a single cell of our complement of a few trillion, to set in motion a chain of events that may result in the growth of a malignant tumour that may kill us. Evolution has provided us with an elaborate set of fail-safe devices that usually obviate this catastrophe, but the sad reality is that some - times even these break down and the result is a single cell freed from the growth constraints that are normally imposed on it as a component of the complex social cellular structure that is a human being. From that moment, that cell and its rapidly expanding progeny (the malignant clone, or cancer) go it alone, as it were, and follow an evolutionary pathway dictated entirely by the survival of the clone, oblivious or even antagonistic to the welfare of the host that spawned them initially. It behaves much like a foreign organism in com - petition with its host, but unlike other foreign organisms this new growth, or neoplasm, is so much like the host immunologically that the immune system fails to recognise it as any kind of a threat, and does little or nothing to curb its growth.

  • Chapter 33 - Cellular Targets of Antiplatelet Agents

  • from SECTION 3 - MOLECULAR THERAPEUTICS
    • By 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., 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.
  • 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 391-395

  • Summary

    INTRODUCTION

    Platelets are anuclear and circulate in the bloodstream as discoid, smooth-surfaced cells about 1–3 μm in diameter. They have a circumferential band of microtubules and two membrane systems, the endoplasmic reticulum or dense tubular system and the plasma membrane-derived surface-connected canalicular system. They also contain alpha granules, dense granules, lysosomes and peroxisomes. The alpha granules contain various poly - peptides including fibrinogen, fibronectin and platelet-derived growth factor (PDGF). Dense granules contain adenosine triphosphate (ATP), adenosine diphosphate (ADP) and calcium ions. Platelets play a major role in thrombosis (formation of a blood clot) and haemostasis (arrest of bleeding) after injury.

    The platelet membrane has receptors that are poised for immediate interaction with specific adhesive proteins when an area of vascular damage is encountered. These receptors mediate adhesion to subendo thelium, followed by platelet activation, aggregation with other platelets and formation of a firm platelet plug at the site of the vascular leak. When platelets moving along the vessel wall encounter an area of denuded endothelium, they adhere to the subendo thelial matrix, undergo a change in shape to a sphere with multiple pseudopods, and spread to increase their area of surface contact. Agonists in the microenvironment interact with specific receptors on the platelet surface. The agonist-receptor binding transmits signals from outside the cell to the interior, generating second messengers that induce protein phosphorylation and ion channels. As a result, there is activation of the contractile proteins, secretion of granule contents, an increase in adhesion, recruitment of additional platelets by aggregation, thrombus formation and haemostasis.

    RECEPTOR-MEDIATED ADHESION

    The platelet membrane contains a number of glycoproteins (GPs) that are receptors for adhesive proteins present both in the vessel wall and in plasma. These GPs have been named from GPI to GPIX. The platelet adhesion receptors include GPIa/IIa for colla gen, GPIc/IIa for fibronectin, GPIb for von Willebrand factor (vWF), GPIIb/IIIa fibrin ogen, vWF, fibronectin and vitronectin. The inter action of platelet GPIb with vWF induces intracellular signalling, resulting in a conformational change and activation of the integrin GPIIb/IIIa. vWF then binds irreversibly to the activated GPIIb/IIIa, producing firm adhesion of the platelet to the vessel wall.

  • Chapter 38 - Pharmacogenetics

  • from SECTION 3 - MOLECULAR THERAPEUTICS
    • By Chrisna Durandt, PhD, obtained her doctorate in medical immunology from the University of Pretoria in 2001 and from 2006 to 2007 was a post-doctoral fellow in the Department of Molecular Medicine, University of Pretoria, under the leadership of Professor Michael Pepper., Sahle M Asfaha, BSc, BSc (Hons), MSc, studied CYP450 pharmacogenetics from 2006 to 2007 (PhD candidate) in the Department of Immunology, Faculty of Health Sciences, University of Pretoria, and was a graduate assistant in the Department of Biology, University of Asmara, from 1999 to 2002., Michael S Pepper, MB ChB, PhD (Geneva), MD (Geneva), is Managing Director, Netcare Institute of Cellular and Molecular Medicine, Extraordinary Professor, Department of Immunology, Faculty of Health Sciences, University of Pretoria, and Professeur Associé, Department of Genetic Medicine and Development, Faculty of Medicine at the University of Geneva, Switzerland.
  • 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 433-437

  • Summary

    INTRODUCTION

    The aim of pharmacogenetic studies is to utilise the inherited genetic differences in drug metabolism among individuals to predict variations in drug efficacy and toxicity. Pharmacogenomics is used as a broader term to include the analysis of all genes in the genome that may influence drug metabolism. Completion of the Human Genome Project and many recent technical advances have attracted much interest to the field of pharmacogenetics. Two principal factors have motivated work in this field: the presence of a large number of adverse drug reactions (ADRs) and the lack of efficacy of certain drugs at conventional doses. ADRs are associated with increased morbidity and mortality, poor compliance, increased hospital stay and re-admissions, all of which contribute to an increase in the cost of treatment.

    One of the main areas of interest in pharmacogenetics is the study of polymorphisms in genes coding for drug-metabolising enzymes, drug transporter proteins and others (genotype) that can lead to differences in enzyme activity (phenotype). Enzyme activity can be classified into four groups: poor (PM), inter mediate (IM), extensive (EM) and ultrarapid (UM) metabolisers. UMs have three or more copies of the active gene. These multiple copies result in abnormally high levels of enzyme activity. EM refers to normal subjects who have one or two functional copies of the gene in question and display predicted levels of enzyme activity. IM refers to subjects with one non-functional allele, resulting in reduced enzyme activity. The distinction between EMs and IMs is not completely clear, as some groups consider subjects with one functional copy as IM instead of EM. PMs are subjects with two non-functional alleles and who have no enzyme activity.

    DRUG-METABOLISING ENZYMES

    Drug metabolism can be defined as the enzymatic biochemical transformation of lipophilic drugs into polar and readily excretable metabolites. Although its major role is detoxification and elimination of drugs and other xenobiotics, metabolism can also transform prodrugs and procarcinogens into active therapeutic and potent carcinogenic com pounds. There are more than 30 families of drug-metabolising enzymes and they can be divided into two groups, namely phase I and phase II enzymes.

  • Chapter 7c - Cellular Phenotyping and Flow Cytometry

  • from Chapter 7 - Tools of Molecular Medicine
    • By Lesley E Scott, PhD (Molecular Medicine), is a senior research and development scientist in the Division of Molecular Medicine and Haematology. She focuses on designing, developing and validating molecular diagnostic/monitoring assays designed to achieve affordable CD4 and viral load testing for HIV/AIDS. She is developing a novel statistical model for method comparison., Debbie K Glencross, MB BCh, MMed (Haematology) is associate Professor in the Division of Molecular Medicine and Haematology, University of the Witwatersrand. She has an extensive flow cytometry background including both leukaemia diagnostics and development of affordable PLG-CD4 laboratory monitoring of HIV/AIDS. She has received several awards including a NSTF (National Science and Technology), a Gold NPI (National Productivity Institute) and a JPMorgan Chase Health (USA) award.
  • 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 95-101

  • Summary

    INTRODUCTION

    A blood film prepared on a glass slide and stained with a coloured dye can be viewed under a microscope as in Figure 1. The microscope uses a light source to illuminate the slide to visualise many of the cellular components in blood such as red and white blood cells and platelets. Through the objectives the cellular components of blood are magnified and detail of the blood cells can be determined. This is the basis for histochemistry and is still widely used today. The technique called flow cytometry is in a sense the big brother to micro - scopy visualisation of blood. The light source in a flow cytometer is a laser that is more power ful than a microscope's light globe and the objectives are replaced by very sensitive light (photon) detectors, filters and mirrors. Flow cytometry is the study of cells (cytometry) like microscopy but in suspension (flow), and can investigate many more parameters of the cells all at once. In fact a flow cytometer can analyse more than 1000 events per second and store five and more parameters per event at one time.

    This speed and increased information makes the flow cytometry technology attractive for research and pathology labora - tory services. Several scientific advances (fluor escent protein labelling in the 1940s; hybridoma cell fusion for monoclonal antibody reagent production in the 1980s; the development of cytofluorometer instru - men tation in the 1950s; and the design of air-cooled lasers combined with advanced, user-friendly software for personal computers in the 1960s) have made this technology available as ‘bench-top’ instruments.

    A further very important advance is the organisation of the CD (clusters of differen - tiation) antigens. Several research laboratories the world over were producing monoclonal antibodies against different antigen epitopes on cell membranes and intracellular proteins.

    Monoclonal antibodies are monovalent (to a single epitope) antibodies generated by an immortal hybridoma cell in tissue culture. The hybridoma cell is a fusion partner established and maintained in tissue culture between a plasma B cell and a myeloma cell. This partnership ensures continual secretion of antibodies all with the same antigen binding recognition site. Each monoclonal antibody that was manufactured had a unique name, which made comparative research on the same antigen very difficult.

  • Chapter 5 - Genetic Variation

  • from Section 1 - Principles Of Cellular And Molecular Biology
    • By Silke Arndt, MSc, graduated in 1997 from the University of Bielefeld (Germany). She is currently employed as medical scientist and lecturer in the Division of Human Genetics at the National Health Laboratory Service (NHLS) and University of the Witwatersrand., 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.
  • 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 50-60

  • Summary

    INTRODUCTION

    If an average novel contains about 1000 words per page and the DNA nucleotide sequence of a single germ cell was printed as a book (each nucleotide as one letter), it would result in a tome of about half a million pages! There would be no page numbers, only ‘chapters’ equivalent to our chromosomes. In order to describe the exact position as well as the different kinds of ‘printing error’ that such a vast book may have, a set of universally applied rules is needed. This chapter reviews the spectrum of variation observed in the human genome and briefly outlines a nomenclature for its description specifically related to disease. The nomenclature is based on recommendations from the Human Genome Variation Society (HGVS) published in August 2006.

    WHAT IS A VARIANT?

    A variant is defined as a structural change in genomic DNA that can be transmitted from one cell to its daughter cell. Strictly speaking, mutational events in humans create new alleles, but in this chapter the term variant will be used in place of allele most of the time. It is general practice to use the term mutation when referring to pathogenic variants, though this is not strictly correct. The term mutation is rooted in the Latin verb mutare – to change – and it refers to any change observed in DNA, pathogenic and non-pathogenic.

    HOW DO VARIANTS ARISE?

    The main underlying mechanisms through which variants arise include chromosome breakage followed by the loss of DNA or incorrect joining of broken ends, recombination between misaligned chromosomes, gene conversion and errors made during DNA replication and DNA repair. Variants can arise from the incorporation of ‘wrong’ nucleotides during DNA replication, which can occur spontaneously or result from the presence of chemically modified bases in the template DNA. An additional source of variants is the slippage of nascent DNA strands along their template strands during DNA replication.

    The rate at which variants are produced can be increased through exposure to mutagens present in the environment (e.g. UV radiation and chemical agents) as well as by the presence of ‘faulty’ DNA replication machinery (e.g. DNA polymerase) that does not copy or proofread newly formed DNA stringently.

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