Boerhaave Series for Postgraduate Medical Education – serie

The course of history is never one of smooth progression. Periods of relative quietness are interrupted by periods of wars and revolution. This pattern resembles that of a river which, before flowing into the delta, has to pass countless rapids. The same holds for the development of the science of medicine. In obstetrics some of these 'revolutions' or 'rapids' consist of the introduction of conservative obstetrical treatment by Lucas Johann Boer at the beginning of the nineteenth century, the discovery of the cause of puerperal sepsis by Oliver Wendell Holmes and Semmelweiss between 1843 and 1847, the introduction of the principle of asepsis by Pasteur in 1874, the introduction of prenatal care at the end of the nine­ teenth and the beginning of the twentieth century (Mijnlieff, Treub, De Snoo), the improvement of surgical techniques, the possibility to treat shock by bloodtransfusion, and, finally, the acquisition of new means for the effective therapy of infection. All these developments have led to a sharp reduction of maternal and perinatal mortality. In this connection it must be pointed out that such a reduction could never have been accomplished without the favourable social changes as a result of which medical and prenatal care could be made universally available. In recent years there has been another revolutionary develop­ ment in obstetrics. Two factors have been responsible for this: the ap­ plication of basic sciences in obstetrics, and the dissolution of the isolation with respect to other clinical disciplines.

Views and attitudes. towards termination of pregnancy have shown con­ siderable evolution over the past few decades. Along with these changes has come a growing concern to adopt means and methods which could make termination easier, safer and more effective. In this evolution, termination in the second trimester in par~icular is notable as being responsible for a dis­ proportionate share ofthe complications and adverse experiences associated with pregnancy termination. Although the almost universal shift towards earlier abortion has reduced the number of second trimester procedures as a percentage of the whole, the problems of interrupting pregnancy in the second trimester remain conspicuous. Delay in either seeking or obtaining abortion is still, in many parts of the world, all too frequent. AdditiDnally, recent developments in the prenatal diagnosis of fetal malformations, alphafeto­ protein screening programmes and changes in the pattern of and approaches to intrauterine fetal death now also place greater emphasis on the need for adequate methods of interrupting pregnancy in the second trimester. Unlike the first trimester in which vacuum aspiration is universally con­ sidered to be the method of choice, in the second trimester of pregnancy the clinician is faced with alternatives; one method may be more appropriate than another in a particular circumstance and no single method is unequivocall~ accepted as best. Neither do second trimester terminations form a neatly defined single category.

This book reflects the proceedings of the Boerhaave Course, "Developments in drugs used in Anaesthesia", held on r'lay 7th and 8th 1981 at Leiden University. The goal of the organizers of the course was to obtain a better under­ standing of the pharmacological and clinical applications of the drugs used in the field of Anaesthesiology. In my opinion, there is a constant need for post-graduate teaching not only on a clinical basis, but also in the so-called "basic sciences". This especially applies to anaesthetists. I would like to express my thanks to the speakers, who were all so kind as to send their manuscripts in time for publishing, and to thank the co-editors of this book, as well as rtr. B.P. Ccmnandeur, from r'lar­ tinus Nijhoff Publishers for their fruitful co-operation. Last but not least, I would like to thank the secretarial staff of my depar~ent for all the work they did arranging for manuscripts to be in the right places at the right times. Joh. Spierdijk THE USE OF H2 BLOCKERS T.H. STANLEY In the last decade a new important histamine receptor, H2 receptor, has been discovered which has major importance in gastric acid production. In addition, a new drug Cimetidine (Tagamet) which blocks the H2 receptor has been synthesized. The object of this presentation will be to discuss the possible role of this interesting drug (Cimetidine) before and during operation and possible postoperatively as well.

W. TH. DAEMS This volume contains the papers presented at a Boerhaave Course for Post­ graduate Education on The cell-biological aspects of disease: the plasma membrane and lysosomes. One of the purposes of this introduction is to explain the reasons for this choice of subject. The first question which might be asked - why a postgraduate course on the cell biological aspects of disease was considered neccessary - is not difficult to answer: the impact of the basic sciences on medicine is im­ measurably strong, and among these sciences cell biology has contributed immensely to the advances made in medicine during recent decades. It has provided clues leading to general insights into etiology and pathogenesis as well as to the development of diagnostic tools and a basis for therapeutic methods. These insights derived mainly from the still-increasing body of knowledge about the architecture of cells. Initially, this knowledge arose from the notion that cells are either simply bags full of enzymes or complex sponge like structures in which all organelles are permanently interconnected (Fig. 1). Later, this notion was replaced by a highly schematized picture of the cell as an essentially two-compartment structure (Fig. 2) in which cell organelles are discrete units separated from each other by membranes, enabling each organelle to maintain an internal microenvironment with optimal conditions for its specific metabolic pro­ cesses.

This book is based on a series of lectures given by an international team as part of a course on Bone Scintigraphy organized by the Boerhaave Committe for Postgraduate Medical Education (Leiden, January 1980). Bone scintigraphy and the use of radionuclide tracers in the investi­ gation of skeletal pathology has developed into a subject of its own. Significant advances in instrumentation, radiopharmaceuticals and data analysis has considerably widened the scope of clinical application. Beyond the important area of sensitive detection of malignant involve­ ment of the skeleton, major strides are being made in the investigation of benign bone disease and its metabolic aspects. The structure of this Boerhaave Course reflects this change, with considerable emphasis being given to the discussion of recent methods for tracer uptake quantitation, the discussion of inflammatory osseous disease, benign pathology in general and the investigation of metabolic bone disease. As a clinical tool, bone scintigraphy is present today in most if not all general and regional hospital institutions. It is a technique in demand by genera1 interns, surgeons, radiologists, paediatricians, oncologists and radiotherapists. New areas of application are being evaluated and to some extent consolidated. These include the difficult orthopaedic issues of bone avascularity, prosthesis loosening, infection and non-apparent fractures. A range of new techniques are available and applied to the follow-up of osteomalacia, osteoporosis, osteodystrophy and other con­ ditions where a more objective and even preferably a numerical approach is being explored.

There continue to be disagreements concerning the embryology of the ventric­ ular septum and the nomenclature of its various parts, as well as on its phylogenetic derivation. It must be obvious that until such time as these uncertainties have been resolved it will not be possible to understand the pathogenesis of ventricular septal defects and other anomalies involving the ventricular septum. In an effort to clarify some of these difficulties a number of individuals, including anatomists, embryologists, pathologists, cardiologists, and sur­ geons, all acknowledged experts in their respective fields of endeavor, were invited to present their views and concepts in sessions devoted to the ventric­ ular septum. In this "Boerhaave Course", detailed descriptions of the normal anatomy, embryology, and phylogeny of the septum were followed by papers on ventricular septal defects, atrioventricular defects, straddling valves, and various forms of univentricular heart. Major contributions were made through clinical accounts of these anomalies. This course again clearly demonstrated the value of and the need for a multidisciplinary approach to the recognition, understanding, diagnosis, and management of congenital cardiac disease. While obviously it could not be ex­ pected that all of the problems and uncertainties concerning the normal and abnormal ventricular septum would be resolved, the lively and frank dis­ cussions among all participants of the course undoubtedly contributed to a better understanding of the still existing difficulties. All ofthe contributors to this monograph should be congratulated for a job superbly well done.

During the last five years the histological classification of the non-Hodgkin lymphomas has become a complex subject. Even experienced pathologists and clinicians find it increasingly difficult to make their way through the extensive and often confusing literature. The confusion is mainly due to the fact that different "schools" use different starting points for their classifica­ tion. Moreover, since many immunological problems related to classifica­ tion have not been completely resolved yet, even researchers who use the same approach do not always arrive at the same classification scheme. This book represents an attempt to find common elements in three most important classifications for non-Hodgkin lymphomas (the Rappaport classification, the Lukes-Collins classification and the Kiel classification) and to provide a scientific basis for the classification of this disease group. It therefore defines the two main groups of lymphocytes and their specific distribution pattern in the lymphoid organs and discusses the methods by which these cells and related tumors can be recognized. The various malignant B- and T-cell lymphomas are described in detail by expert authors, who deal not only with the morphological details, but also with the relevant clinical aspects. Finally, some related special topics are dealt with to complete the contents of this book. SECTION I BASIC CONCEPTS AND METHODOLOGY IN LYMPHOMA CLASSIFICA TION 1. HISTOPHYSIOLOGY OF NORMAL LYMPHOID TISSUE AND IMMUNE REACTIONS P. NIEUWENHUIS AND K. LENNERT INTRODUCTION Not so long ago (1) the lymphocyte was defined as:" . . .

The Boerhaave Committee for postgraduate Medical Education decided to organize a course on cancer treatment covering selected solid tumors, in which they felt important chan­ ges were emerging in the basic biologic, diagnostic and therapeutic concepts. Current management of cancer patients is intimately dependent on precise morphologic diagnosis, clinical staging and the proper application of all treat­ ment modalities. Many prominent investigators and clinicians of major can­ cer centers in the United States, Canada, and Europe con­ tributed by lecturing and during the panel discussions. This book is the tangible outcome of the productive ex­ changes during the meeting held December 6-8, 1979. In ovarian cancer the usefulness of histologic grading in determining prognosis has become clear. The most impor­ tant advance for the management of the patient is th- careful staging procedure, based on new concepts of tumor spread coupled with treatment tailored to the extent of disease. Survival appears to be directly related to the extent of the tumor mass. This has resulted in description and application of optimal cyto-reductive surgery. Radiotherapy and chemotherapy can both effectively eradi­ cate small amounts of tumor.

This book is based on the proceedings of a successful Boerhaave International Symposium on colorectal cancer held at the University of Leiden, 6-9 June, 1979. I would like to offer grateful thanks to the eminent clinicians and scientists who contributed both to the Symposium and to this book. Colorectal cancer is a very common form of malignancy, particularly in the Western world, and there have been a number of recent developments in the management of this condition. This book has attempted to collate informa­ tion on the current methods of investigation and treatment and I believe that it will prove valuable to all those interested in oncology. The contents range widely, covering the entire field from epidemiology through screening methods, diagnostic approaches and therapy of both primary and secondary disease. Perhaps the most outstanding new areas discussed and reflected in the proceedings are the possible range and scope of screening techniques, the new possibilities both in treatment and in endoscopic surgery now available as a result of developments in fibre-optic endoscopy, and new approaches and important parameters in staging of the disease.

The desirability of quality-assay of ingestable or imbibable material has resulted in an established procedure in advanced countries. Testimony to its necessity was borne by the scandal of chateau-bottled Bordeaux crus classes a few years ago, a litigation instigated by the disillusioned consumers who either on the basis of absence of the expected inebriate state, or of the olfacto-gustatory caress by the bouquet or full-bodied lingering pharyngeal sensation, decided to strike a paranoid attitude, which ultimately proved to be justified. When one proceeds from sheer pleasure to dire necessity, the question of what happens to ingested medication assumes quite portentous features. Testimony is borne to this by the transitional stage, at which one is faced with the legal consequences of the basically illegal alcohol-respiration test, based on the relationship between the amount of ingested alcohol and the C Hs OH concentration in expired air or in venous blood, a wholly uncon­ 2 stitutional terror, in view of the Rome treaty signed by the Western coun­ tries, which says that nobody should be required to cooperate in procedures aimed at providing him guilty. On top of this, the lamentable fact is observ­ able, that among the professio nobile there are even those who took the oath of Hippocrates and lend their hands, not to cure (as they promised), but to perform a cubital vein puncture in order to prove someone, who is not their patient, guilty.

In recent years there has been an impressive surge of interest in the mecha­ nisms which control the onset and the maintenance of labour. Much of it stems from a constant awareness that gestational age at birth is still an important factor in neonatal mortality and morbidity. Advances in the sensitivity and specificity of immunoassay, the discovery of the prosta­ glandins, new skills in fetal surgery and chronic catheterisation in experi­ mental animals have greatly stimulated further research in this area. In the meantime clinicians became continuously more aware that, despite consider­ able advances in perinatal medicine, gestational age at birth remains the major determinant of neonatal mortality and morbidity. It led them to seek new and better ways of controlling uterine function whether by influencing cervical ripeness, by stimulating or by inhibiting myometrial contractility. This volume uniquely combines knowledge which has been gained from both experimental and clinical research on parturition. A brief outline of current evidence on the control of parturition in experimental animals may be fruitful in delineating problems and hypotheses for further study in human pregnancy. Much of our present day knowledge of human parturition has been gained by checking such data against experimental findings, careful measurements and clinical observations in human pregnancy. It is hoped that the interdisciplinary nature of this volume will enhance the understanding of human parturition and stimulate further research in this area. Thanks are due to Miss H. Wittenberg and Mrs M.

The material contained in this book was presented at the Boerhaave Course which was held in Leiden, The Netherlands, on May 2 and 3, 1977. It deals with three topics of considerably recent interest, not only to cardiologists and cardiovascular surgeons, but also to embryologists, anatomists and pathologists. Papers on the development and the normal anatomy of the conduction system include a discussion of the continuing controversy as to whether dis­ crete and anatomically distinct internodal pathways exist in the human heart. These are followed by descriptions of the abnormal anatomy and relation­ ships of the conduction system in certain complex cardiovascular anomalies. The rather startling discovery that there may be a second, ectopically located and functioning atrioventricular node and common bundle in addition to the usual, but non-functioning one has been of enormous importance in the surgical treatment of certain forms of congenital heart disease. The panel presentations comprising the first four papers on the topic of transposition of the great arteries highlight the widely differing views atld the continuing controversies concerning the nature and pathogenesis of this rela­ tively common and important anomaly. Descriptions of the special morpho­ logic features of ventricular septal defect and pulmonary stenosis as they occur in association with transposition are followed by discussions concern­ ing recent advances in the surgical treatment of transposition, and the com­ mon and often troublesome postoperative arrhythmias.

Every specialist, at present, is confronted with the fact that it is continually becoming more difficult to remain 'up to date'. The areas in which he must read are expanding while the individual publications are becoming greater in number, larger in content and appear more frequently. The choice of the subject was not easy. This time we have selected the pharmacological aspects of anaesthesiology as our main topic, as a continu­ ation of the Boerhaave course in 1971. Although we know that a drug works, the mechanism behind this action is of great importance. The pharmacokinetics and side effects of the drugs we administer affect not only our patients, but also ourselves, our children, and the personnel under our care. In a special section we draw attention to this subject. We fervently hope that this symposium will further enrich your knowledge of anaesthesia and that through this enrichment you will derive more pleasure from the profession you have chosen and that in the end this will lead to even better care and treatment of the patients entrusted to us. We wish to express our thanks to Prof. C. M. Conway, Dr. D. T. Popescu, and Prof. D. M. E. Vermeulen-Cranch for their assistance in the editing of some of the chapters in this book.

One of the most fascinating tools at the disposal of the molecular biologist is the medical clinic. The responsibilities of those who provide health care do not stop when they give optimal care to the individual patient and train their successors adequately. They also are under the obligation to obtain maximal information from every case they treat in order to reach a better understanding of the underlying illness in order to improve therapeutic results in the next patient. Fundamental research in pathological material is therefore a medical must as well as an opportunity for scientific work. The scientist working in this field can profit from nature's unasked for experiments, which are encountered by his medical colleagues in their clinical material. There are many examples of subjects of study - for instance hemoglobins and immunoglobulins - which started in a medical context and gradually developed into a field of prime interest for the molecular biologist. The study of blood coagulation is one of the younger areas of this kind.

The present volume of the Boerhaave series intends to be a reflexion of our present knowledge in the expanding field of early diagnosis and prevention of inherited disorders. Early diagnosis can mean detection of a carrier state in one or both potential parents, detection of a specific inherited disease in a previously born child or during a pregnancy at risk, or during various stages of the life of an already born individual. The first chapters will discuss inherited disorders manifesting later in life. In Huntington's Chorea detection may be possible from the age of 20 or 30 onwards, while in myotonic dystrophy it will be seen that detection may be possible soon after birth. Retinoblastoma serves as example of a disease manifesting in early infancy and which is partially treatable by surgical intervention. The same early onset does occur in phenylketonuria and cystic fibrosis. Both diseases provide examples of the possibilities of population screening, while in phenylketonuria an eminently succesful treatment is found in a restricted diet. For the usually early manifesting sphingolipidoses no treatment exists as yet, but enzyme treatment might in the near future become a reality. Spina bifida and anencephaly are not simple inherited Mendelian dis­ orders but they are discussed in this volume because prevention is possible by antenatal diagnosis and subsequent interruption of the pregnancy if re­ quested by the future parents. Further views on antenatal diagnosis notably in inborn errors of metabolism are presented in a following chapter.

The 1973 Boerhaave Course in Leiden on Measurement in Anaesthesia was composed of the lectures included in this book, supplemented by the series of 'lecture demonstrations' organised by Dr. P. Cliffe and given by the members of the Departments of Clinical Measurement and the Magill Department of Anaesthetics, Westminster Hospital, London. The aim of the 1973 Boerhaave Course on Measurement in Anaesthesia was designed to arouse interest in this subject where it has not already occurred. The subjects discussed in the lectures and presented in this book were those that were considered topical and appropriate. The lectures were meant to give an idea of some basic and advanced possibilities of measurement. It was not intended to be an exhaustive review of all the measurements relevant to anaesthetic practice and research. In this time of monitoring one has to keep in mind that good measurement is the basis of good monitoring. A certain amount of repetition is unavoidable as each lecture was intended to be complete in itsel. However, editing has reduced this to a minimum. Department of Anaesthesiology Johan Spierdijk University Hospital, Leiden Department of Anaesthetics Stanley Feldman Westminster Hospital, London Julian Leigh CONTENTS Preface ... V Contributors VIII PART ONE INTRODUCTION The difference between measurement and monitoring. What is worth measuring? . . . . . . . . . . . . . . . . . . . .. . . . 3 . JOH. SPIERDUK and A. NANDORFF Problems of interference and electrical safety associated with the - cording of biological signals . . . . . . . . . . . . . .. . . . 13 J. P. BLACKBURN 22 The scope of measurements using radioactive isotopes .

This volume contains the proceedings of a postgraduate course for medical practitioners of various specialties. One purpose of the course was to provide factual data on developmental aspects of the brain and behaviour, and about the possible impact of several important categories of internal and environ­ mental factors upon neural development. Another purpose was to indicate the extent and the limitations of the methodology now available for the scientific approach of the study of the development of behaviour. In general the investigator is faced with methodological problems of two types, the proper definition and scoring of behavioural items, and the isolation of the different factors that contribute to a particular behaviour. An example of the latter is given in the very last paper, which is concerned with attempts at unravelling under experimental conditions the contributions made by various influences upon a single sequence of behaviour. The course was held in Leiden in November 1970, and was the third in a series of Boerhaave Courses instigated by the Dutch Growth Foundation. Previous subjects have been 'Somatic growth of the child' (in 1964) and 'Human body composition' (in 1967). The programme was planned in collaboration with Prof. Dr. H. H. van Gelderen, Dr. D. G. Lawrence, Prof. Dr. F. J. Monks, Prof. Dr. H. F. R. Prechtl and Prof. Dr. H. K. A. Visser. Financial support was given by the pharmaceutical firms Philips-Duphar, Sandoz and Specia, and by the Dutch Growth Foundation. Major editorial contributions were made by Anneke Bot.

During the past twenty years there has been a rapid evolution in anaesthesia, so much so, that we stand on the brink of a major change in the role of the anaesthetist in medicine. Anaesthesia has now emerged from being a craft speciality, obsessed with details of techniques, to become a science concerned with the maintenance of life. As a result of our better understanding of the physiological and pharmacological effects of anaesthesia and surgery, new opportunities have been created for anaesthetists to apply their particular knowledge, not only to provide better and safer conditions for surgery, but also in resuscitation, ventilatory and circulatory support and in the treatment of chronic pain. This has resulted in the recognition of the anaesthetist as a physician specialising in applied physiology and clinical pharmacology. The 1971 Boerhaave Course in Anaesthesia has deliberately tried to reflect this scientific basis of the speciality of anaesthesia by selecting for presenta­ tion in this book, subjects in which recent investigations have provoked new concepts and ideas. We are most grateful to our colleagues who presented a paper and to the secretary-staffs of our departments of anaesthesia in Leiden and London. Also thanks are extended to Mrs. Bongertman for the preparation of the proofs. Department of Anaesthesiology 10han Spierdijk University Hospital, Leiden Department of Anaesthetics Stanley Feldman Westminster Hospital, London v CONTENTS Preface . . . V Contributors . VIII PART ONE ANAESTHESIA AND THE HEART Alpha and beta blockers in anaesthesia . 3 H. LABORIT 18 Advantages and disadvantages of isoprenaline .

This book comprises the essential records from a Boerhaave course given in June 1971 for specialists in cardiology and other fields of internal medicine interested in the subject of quantitation in cardiology. It is evident that in the wide field of medicine, and particularly in cardiology, there is a growing need for exact and detailed information in conjunction with existing diag­ nostic methods. This is apparent in the greater precision in anatomical and haemodynamic details required by the thoracic surgeon as the number of available heart operations gradually increases. In retrospect it is hardly surprising that the high initial mortality after the introduction of each operation depended to a large extent upon the degree of accuracy with which the diagnosis was made. Another urgent need for precise and quantitative information became apparent when monitoring of high-risk patients, in order to forestall compli­ cations and/or death, became routine. The same applies for the diagnostic procedures used to estimate the patient's chances of surviving an operation and/or rehabilitation after a serious incident, such as myocardial infarction. In these fields there is a vast amount of data to be handled and - in modern diagnostic procedures - it must be processed so rapidly that the human mind cannot suffice and computer equipment has becomeindispensable.

The course of history is never one of smooth progression. Periods of relative quietness are interrupted by periods of wars and revolution. This pattern resembles that of a river which, before flowing into the delta, has to pass countless rapids. The same holds for the development of the science of medicine. In obstetrics some of these 'revolutions' or 'rapids' consist of the introduction of conservative obstetrical treatment by Lucas Johann Boer at the beginning of the nineteenth century, the discovery of the cause of puerperal sepsis by Oliver Wendell Holmes and Semmelweiss between 1843 and 1847, the introduction of the principle of asepsis by Pasteur in 1874, the introduction of prenatal care at the end of the nine­ teenth and the beginning of the twentieth century (Mijnlieff, Treub, De Snoo), the improvement of surgical techniques, the possibility to treat shock by bloodtransfusion, and, finally, the acquisition of new means for the effective therapy of infection. All these developments have led to a sharp reduction of maternal and perinatal mortality. In this connection it must be pointed out that such a reduction could never have been accomplished without the favourable social changes as a result of which medical and prenatal care could be made universally available. In recent years there has been another revolutionary develop­ ment in obstetrics. Two factors have been responsible for this: the ap­ plication of basic sciences in obstetrics, and the dissolution of the isolation with respect to other clinical disciplines.

The Leiden-Edinburgh Boerhaave Course on 'The Gastro-intestinal Tract', held in Leiden on October 29 and 30, 1969, resulted from the renewed co-operation between the Medical Faculties of Edinburgh and Leiden, based on very old ties. As one will know, the Edinburgh Faculty of Medi­ cine was founded in 1726 on the principles guiding the Leiden Faculty of Medicine at that time, on the instigation of John Monro I, who had studied medicine in Leiden under the famous Boerhaave. These old ties were revived some 8 years ago, first by students, later by the Faculties themselves, with the special purpose to facilitate and en­ large the exchange of medical knowledge between two medical centres. One of the results of this was that it was considered whether physicians from both countries could not profit from the knowledge gained specific­ ally in both these faculties by letting the investigators from both faculties tell about their work within the framework of courses for post-academic medical training, in Leiden called the 'Boerhaave Courses'.

The Boerhaave Courses in Cardiology have been held once or twice a year since 1955. For the greater part they were meant for specialists in Cardiology, Pediatrics, and Internal Medicine, who wished to hear about recent advances in Cardiology and in its anatomical and physical basis. For some time the courses reflected mostly the work in Leiden, especially on congenital heart disease, but soon the highly valuable cooperation of other centres was obtained on subjects in which they had more experience. In later years speakers from abroad were also invited and they con­ tributed greatly to the wider scope of the courses. It was thus possible to organize detailed discussions on special subjects by panels of experts for an audience of interested clinical specialists. General reviews were also given for widely varying groups including general practioners and health officers. The special courses were usually given in English and were international in character, while the general courses were given in Dutch. This book reports on a course that united both trends. It was held entirely in English mainly because it was combined with a meeting organized by the Dutch Heart Association and because of the support given by the Secretary of Health who opened this meeting personally and by the European branch of the World Health Organization which was represented by Dr. Pisa.