Over recent years, much renal research has focused on the pathology of the glomerulus, where many primary renal insults occur. However, nearly thirty years have passed since Risdon's study made the apparently anomalous observation that the extent of damage to the tubulointerstitial compartment is the major determinant of renal outcome in a variety of human glomerular diseases. This volume covers various aspects of tubulointerstitial disease, and starts with an update on cystic disease of the kidney, by Drs. WILSON and FALKENSTEIN, which includes recent experimental data on the altered properties of cystic epithelium. My own chapter gives an overview of the mechanisms of tubulo interstitial damage in progressive renal disease and includes a dis cussion of the possible role of cytokines, vasoactive peptides and peptide growth factors found over the last few years to be secreted by renal tubular cells. These comments are expanded in the contribution by Dr. WOLF and Professor NEILSON, who provide a detailed account of the cellular biology of tubulointerstitial growth. The earliest studies from the 19608 attempted to correlate histo morphometry of the tubulointerstitium with renal outcome. Dr. KHAN and Professor SINNIAH provide us with an update on mor phometric methods as applied to the kidney using new techniques. Similar techniques are employed by Dr. IVANYI and Professor OLSEN who give a detailed stereomorphological account of tubulitis both in acute allograft rejection, where its- recognition is central to the diagnosis, and in other forms of tubulointerstitial disease."

Close cooperation between those involved in clinical treatment and pathology is imperative in head and neck surgery, as in all surgical fields. The degree of cooperation depends, on the one hand, on the knowledge that the head and neck surgeon has about the possibilities and limits that confront the pathologist, and on the other hand, on the knowledge that the pathologist has about the special problems of head and neck pathology and their management by the surgeon. Within the last 15 years, the knowledge of larynx growths and their treatment has changed rapidly. Parallel to this increase in knowledge, the technical possibilities in histopathology have also increased. For this reason, the authors of this volume present an up-to-date view of the whole scope of the pathology and clinical treatment of larynx tumours.

The early development of the mammalian embryo belongs to a period which, for the student, provides the particularly deep fascination connected with the processes of germination of the fIrst tender buds of life. Moreover, developmental biology encompasses a very large part of biology; if broadly dermed - almost all of it. The same is true for the fIeld of pathology if the manifold possibilities of disorders of the orderly arranged pathways of developmental processes are considered. Normal development in its earliest steps - and it would be diffI cult to see it otherwise - means the functioning of very intricate systems of complex inter dependent cycles controlled by structural, genetic, physiological and biochemical determi nants. However, disturbances interfering with them in their very different ways, can lead to fetal death, disorders of growth and differentiation, malformation and disease, sometimes as late as in the next generation or later. This is, indeed, the concern of the pathologist to whom and to whose interest in developmental pathology, this book is dedicated. The outlines of the present volume were conceived at a symposium on "Control of early em bryogenesis and factors responsible for failure of embryonic development" held May 1-4, 1974 in Travemtinde and sponsored by the Deutsche Forschungsgemeinschaft. Almost fIfty active participants attended this conference. At the time and in keeping with the purpose of the conference, publication of the proceedings was not envisaged."

Advances in biochemistry, cell biology, genome-wide mutagenesis - coupled with molecular technology, including gene microarray and transgenic and knock-out animals - have been instrumental in understanding the cellular processes and molecular pathways of self-tolerance and autoimmune diseases. The molecular definition of these pathways and processes has led to novel treatments for certain auto-immune diseases that are based on the pathogenesis of diseases rather than on broad-spectrum immunosuppression. This book reviews many of these current developments and proposes future novel approaches for understanding the pathogenesis of auto-immune diseases and designing novel therapy. This book covers three major areas of auto-immunity: the basic mechanisms of immunological tolerance, pathogenesis of auto-immune diseases, and some novel therapies. This book should be useful for immunologists, molecular biologists, rheumatologists, and clinical scientists.

The origins of this book go back to the first electron microscopic studies of the central nervous system. The cerebellar cortex was from the first an object of close study in the electron microscope, repeating in modern cytology and neuroanatomy the role it had in the hands of RAMON y CAJAL at the end of the nineteenth century. The senior author vividly remembers a day early in 1953 when GEORGE PALADE, with whom he was then working, showed him an electron micrograph of a cerebellar glomerulus, saying "That is what the synapse should look like. " It is true that the tissue was swollen and the mitochondria were exploded, but all of the essentials of synaptic structure were visible. At that time small fragments of tissue, fixed by immersion in osmium tetroxide and embedded in methacrylate, were laboriously sectioned with glass knives without any predetermined orientation and then examined in the electron microscope. After much searching, favorably preserved areas' were studied at the cytological level in order to recognize the parts of neurons and characterize them. Such procedures, dependent upon random sections and uncontrollable selection by a highly erratic technique of preservation, precluded any systematic investigation of the organization of a particular nucleus or region of the central nervous system. It was difficult enough to distinguish neurons from the neuroglia.

During the past years a considerable number of books have been published on atherosclerosis research. Much attention has been focused on the biochemical properties of lipoproteins and the involvement of lipoprotein metabolism in the atherogenic process. The monograph presented here focuses on morphologic studies of atherosclerotic plaque. One chapter deals with the pathobiochemical changes in the arterial wall at the inception of atherosclerosis. Recently the specific role of macro phages in atherogenesis has been the object of much interest. A morphological study of their role and differentiation is the topic of another chapter. This is complemented by a study of lipoprotein receptors on macrophages and smooth muscle cells both in cell culture and in situ, based on electron microscopic investiga- tions. An immunohistological study on the in situ localization promotes our understanding oflipoprotein metabolism in the arterial wall. The morphologic aspects of more advanced lesions are present- ed in studies of collagens and angiogenic processes in the athero- sclerotic vessel wall. Experimental investigations have also been useful for understanding the pathogenetic aspects of atherosclerosis; one crrapter concentrates on the metabolism of fibromuscular and atheromatous plaques in an experimental model. A final chapter deals with transplant arteriopathy and its possible parallels with conventional atherosclerosis. The widespread discussion of athero- genesis is focused on the arterial wall and its morphological alter- ations, emphasizing once again the importance of morphological research for understanding the pathological basis of disease. Borstel and Magdeburg E. VOLLMER and A.

With the introduction of antibiotics acute inflammatory disease has ceased to be the dominant problem in general medical practice and its place is now increasingly occupied by chronic inflamma tory disease of which the rheumatic diseases constitute the most important group. lwo aspects of these diseases need to be consid ered, their aetiology and their pathogenesis. In some respects the latter is more important since even when the aetiology is known, as for example the haemolytic streptococcus in rheumatic fever, the mechanism by which the infecting agent accomplishes the development of the lesions that characterise the disease are still largely unknown. Still more so is this the case in rheuma toid arthritis and other chronic inflammations where the aetio logical agents are unknown. In an attempt to clarify the pathogenic mechanisms involved, sev eral attempts have been made to induce comparable lesions in ex perimental animals, partly to test underlying hypotheses, and partly to provide test situations for the trial of new therapeu tic agents. In view of the deficiencies in the current drug treat ment of chronic inflammatory disease there are many who feel that this is largely due to the inadequacy of the models avail able for test purposes."

La pathologie vasculaire a ete tres marquee par les progres biologiques de ces vingt demieres annees. Le systeme arteriel est main tenant considere comme un organe a part entiere. Modelee au cours de l'organogenese par les facteurs hemodynamiques, Ie paroi arterielle maintient une structure hautement organisee et des proprietes mecaniques qui dependent directement des conditions de pression et de debit. La monocouche endotheliale developpe 2 une surface de plusieurs centaines de m a l'interface sang-tissu; elle est a la fois un organe endocrine complexe synthetisant de nombreuses proteines qui participent a l'hemostase, une surface thromboresistante et hemocompatible, une barriere de permeabilite contr6lant les echanges sang-tissus. Les cellules musculaires lisses constituent un tissu multifonctionnel, contractile, assurant la synthese des composants structuraux responsables des proprietes mecaniques de la paroi arterielle, la transmission de la force contractile, et une etonnante activite reparatrice en reponse aux agressions. Tout ceci est soumis a un ensemble complexe de communications cellulaires qui font de l'endothelium un veritable systeme recepteur pour la paroi vasculaire. Parallelement, ou a la suite de ces progres, l'angeiologie s'est progressivement affirmee comme une specialite clinique. Debordant Ie cadre de la chirurgie vasculaire, elle integre les concepts physiopathologiques au diagnostic et au traitement des maladies arterielles. De cet effort d'integration est ne cet ouvrage, cherchant a concilier les connaissances fondamentales es plus recentes et la demarche clinique.

Immunology, in all its facets of immunochemistry, humoral immunity, cellular immunity, immunodiagnosis, and immunotherapy, is currently the most rapidly advancing discipline of clinical and experimental oncology. But as in most developing subjects, it is continually beset with problems of methodology and nomenclature, both of which are often intertwined. Indicative of this problem are our circular definitions of antigen and antibody. Another fre quent problem is the use of the words "specific" and "associated" when characterizing re actions to tumors or the antigenic properties of neoplasms. When applied to cancer, these terms are obviously very dependent upon the methods used to demonstrate these qualities. Indeed, the very diverse nature and multitude of types of cancer preclude our making gen eralizations or categorical statements regarding tumor "specificity. " Similar problems arise when one considers that many antigens found in malignant tumors share certain properties with embryonic or fetal tissues. First, these observations emphasize a lack of true tumor specificity, for which reason the category of oncofetal antigens has been established. Second, whether or not such antigens are truly oncofetal depends upon the method of detection used, and it has been found that here too specificity decreases as the antigen assay increases in sen sitivity. Thus, whether substances can be truly oncofetal in nature still remains a matter of debate, and such terms must therefore be used in an operational sense.

The aim of this book is to expand the clinical information given by computed tomograms (CTs) of cerebral infarcts. Anatomical sections are displayed parallel to the CT correlate in the hope that the interpretation of pathogenesis will provide valuable clinical data at a time when the number of angiographies performed in cerebrovascular cases has diminished rapidly. For better understanding of pathogenesis our concepts concerning the process of infarction have been summarized on the basis of schematic draw ings. K.-J. ZULCH KOln Acknowledgments I am most grateful to Professor Hoeffk: en for permission to use computed tomograms from his institution, to Herr GOldner and Frau Miihlhover for their technical assistance, and to Frau Goldner for help during the editorial work. My particular thanks go to my friend Professor W.S. Fields, Houston, who undertook the great burden of styling the English text. My gratitude is expressed to Dr. Dr. h.c. multo Heinz Gotze and Springer Verlag for the excellent layout and quality of this book."

MOTOOMI NAKAMURA As we approach the 21st century, ischemic heart disease is the major cause of death in most of the developed nations of the world. Since the 1970s, much effort and expense have led to designs of coronary thrombolytic therapy, percutaneous coronary angioplasty (PTCA), coronary artery bypass grafting, heart transplantation, automatic defibrillators, as well as to the formation of beta blockers and com pounds which block the calcium channel. Socio-educational programs directed at exercise, diet, instruction in the risk factors of smoking, hyperlipidemia and hypertension have contributed to the decrease in the rate of morbidity and mortality of patients with ischemic heart disease. However, the first clinical event of ischemic heart disease, the so-called "heart attack" and sudden cardiac death continues to present problems, as the mechanisms involved in these events are poorly understood. It has long been thought that ischemic heart disease is the sequence of an organic fixed atherosclerotic obstruction of the epicardial coronary arteries and the role of coronary vasomotion has been given much less attention. Recent clinical and laboratory animal studies revealed that increased tonus and spasm of the large epicardial coronary arteries are the cause of various stages of ischemic heart disease. The role of coronary vasospasm in the development of un stable angina, sudden cardiac death and acute myocardial infarction remains open to debate. Pharmacophysiological studies showed that the epicardial large coronary artery contributes only 5% to regulation of normal coronary flow."

Battle is a practical and sometimes lasting way of solving man's problems. It relies on the strength of the combatants and ignores the truth of the dispute. Discussion face to face can dissolve attitudes which have incorrectly determined judgements. The most striking example of this that I know is a Battle in Ireland in the eleventh century, where the king of Leinster fought a Viking prince. The Icelanders had raided Ireland for several generations in search of women, which they lacked since most of the population of Iceland were men who had arrived there by rowing long-boats from Norway. The prince was leading such a raid for the first time. Standing in the prow of the leading boat he saw Irish cavalry galloping along the beach to meet them. As they approached the shore the Irish king rode out of the band to challenge single combat. The Icelander jumped into the surf to meet him. As they raised their swords each realized that the other's face was like his own. When the Irish king spoke the other recognized the language. It had been spoken in Iceland by his grandmother who had been captured and taken there from Ireland. Swords were dropped and replaced by drinking horns. It was soon established that they were cousins. The battle gave way to a life-time of close co-operation.

This two-volume treatise, the collected effort of more than 50 authors, represents the first comprehensive survey of the chemistry and biology of the set of molecules known as peptide growth factors. Although there have been many symposia on this topic, and numerous publications of reviews dealing with selected subsets of growth factors, the entired field has never been covered in a single treatise. It is essential to do this at the present time, as the number of journal articles on peptide growth factors now makes it almost im anyone person to stay informed on this subject by reading the possible for At the same time it is becoming increasingly apparent that primary literature. these substances are of universal importance in biology and medicine and that the original classification of these molecules, based on the laboratory setting of their discovery, as "growth factors," "lymphokines," "cytokines," or "colony-stimulating factors," was quite artifactual; they are in fact the basis of a common language for intercellular communication. As a set they affect es sentially every cell in the body, and in this regard they provide the basis to develop a unified science of cell biology, germane to all of biomedical research."

Histochemistry deals with the activities of chemical components in cells, and immunohistochemistry addresses the function of cell types in tissue or organs, such as those leading to acceptance or rejection of grafts or organs. This book is a methods volume focusing on antigen retrieval, particularly methods used in disease-related antigens. Because the book is a methods volume and a lab manual, it will have an audience of pathologists, biochemists, and lab technicians.

J. Oort and J. P. A. Baak This manual is written by pathologists and is meant for pathologists. It deals with a subject that became especially popular in pathology at the end of the last decade: morphometry. Morphometry is defined as the quantitative description of a structure (Weibel, 1969). This structure may be both of macroscopic and micro- scopic size. Strictly, the size of an organ is a morphometric feature. This type of morphometry has long been in use in pathology. Examples ofthis type in diagnostic pathology have been given by Roesle and Roulet (1932). In this manual, however, the term morphometry is used in its re- stricted microscopic meaning, i.e., the quantitative description of micro- scopic images and features. The quantitative analysis of microscopic pic- tures has for a long time been subordinated to the qualitative description. This may partly have been caused by the preference of the human mirld for pattern recognition rather than quantitative appraisal, which leads to judgements based on impressions subconsciously tested against the ob- server's (mental) image of the normal pattern. Another cause may have been the time-consuming difficulties of collecting and computing quanti- tative information. During the past decades the usefulness of quantitative methods in histo- and cytopathology has been stressed for many different subjects. In addition, minicomputers have become widely available and are becoming increasingly inexpensive; the more so since the introduction of micro com- puters.

We would like to take this opportunity of expressing our sincerest thanks to the many persons who have made adrenal tissue and related materials available to us for our work. Our especial gratitude is extended to Drs. J. J. Brown, A. Lever and J. I. S. Robertson of the M.R.C. Blood Pressure Unit, Glasgow, Dr. J. K. Grant, Royal Infirmary, Glasgow, Professor R. B. Welbourn and Dr. W. Kelly, Royal Postgraduate Medical School, Drs. D. B. Grant of Great Ormond Street, J. Ginsberg, Royal Free Hospital, D. C. Anderson, Hope Hospital, Salford, C. R. Edwards, St. Bartholomew's Hospital and Professor I. Doniach (for merly of the London Hospital) and Messrs. J.-c. Gazet, A. McKinna and P. Greening, Royal Marsden Hospital, London. The preparation and presentation of the material and the results would not have been possible without the help of Dr. P. Monaghan and his Electron Microscopy Unit, Ludwig Institute for Cancer Research (London Branch), Sutton, Mrs. Mitchell and her Histology Team, Royal Marsden Hospital, Sutton, Mr. K. Moreman of the Photographic Department of the Royal Marsden Hospital and Institute of Cancer Research, London and Mr. M. Hughes for graphics. Particular thanks are due for the untiring efforts and assistance ofMr. J. Ellis and Mrs. D. Corney of the Ludwig Institute for Cancer Research (London Branch), Sutton, for most of the photographic and secretarial work respectively. Professors G. Dhom and E. Mausle kindly provided material for Figs."

In commissioning this volume of Current Topics in Pathology, the editor of the series, Prof. Sir Colin Berry, asked me to produce something "which is aimed at the general pathologist but from the point of view of the neuropathologist who knows what is not being done well." This was easier said than done. Many aspects of neuropathology are encountered only infrequently in general pathology and are best dealt with by re ferral of material to a specialist unit. Others need more extensive investigation than is practicable in a general pathology setting. Yet neurological disorders in general are common and are encountered by general histopathologists, paediatric and forensic pathologists on a daily basis, particularly in autopsy practice. In inviting contributions to this volume of Current Topics in Pathology, I therefore biased the con tents towards disorders in which the conduct of the autopsy and the initial approach to neuropathological investigation are of critical importance in making the diagnosis. The authors all have a wealth of experience and expertise and I believe that this is reflected in their approach, which is both personal and practical. Indeed, the emphasis in this book is very much on the provision of practical advice. All of the chapters contain guidelines on the conduct of autopsies as well as infor mation on the macroscopic and basic histological assessment of the nervous system in the relevant disorders."

Medical imaging is an important topic and plays a key role in robust diagnosis and patient care. It has experienced an explosive growth over the last few years due to imaging modalities such as X-rays, computed tomography (CT), magnetic resonance (MR) imaging, and ultrasound. This book focuses primarily on model-based segmentation techniques, which are applied to cardiac, brain, breast and microscopic cancer cell imaging. It includes contributions from authors working in industry and academia, and presents new material.

The translation of Blood Smears Reinterpreted was begun when the French original was still undergoing revisions. I was accorded the oppor tunity to question any statement or turn of phrase that was unclear to me or appeared liable to misinterpretation. It is my hope that as a result, ambiguities-particularly those inherent in differences between American and Eu ropean usage-have been removed and that I have at least ap proached the ultimate goal of any translation: to reflect the author's intention accurately while remaining as readable as the original. Beyond the role of translator, I was encouraged to assume the role of critic. As a result, some pages or even single sentences were hotly debated, sometimes for hours, as Marcel Bessis insisted that any inter pretations on which we could not agree should be so indicated. In fact our discussion invariably ended in agreement, though they led to changes of a sentence here or a word there and, on occasion, to the addition of a footnote or a brief paragraph.

Sarcomas represent a group of rare tumors which arise from the largest tissue compartment of the body, but account only for about 1 % of all malignancies. Among this group of tumors, soft tissue sarcomas in adults are, in addition to osteosarcomas, the most important. In the diagnostic workup of soft tissue sarcomas modern radiological investigation methods such as CT and MRI techniques are being critically evaluated. While it is widely accepted that the conventional, stained microscopic specimen is still the cornerstone for properly planned treatment stra tegies, immunohistochemistry has come to play an indis pensable role in accurate classification. Reviewing the surgical techniques, the treatment of musculo-skeletal malignancies, especially of soft tissue sarcomas, has changed considerably over the past decades. While amputation used to be the surgical treatment of choice limb-saving procedures have now become an im portant therapeutic modality in treating such lesions, particularly in combination with percutaneous or interstitial radiotherapy. Despite adequate local treatment, many patients with soft tissue sarcomas will ultimately develop metastatic disease, usually in the lungs. For this reason, effective ad juvant systemic treatment should be given simultaneously with or soon after treatment of local disease. The results of several randomized trials evaluating adjuvant chemotherapy have been reported in the meanwhile, indicating im proved, disease-free survival with a trend towards improved overall survival. In disseminated disease, drug combi- VI Preface nations or single agents are used as palliative treatment and might help to improve survival in selected subgroups."

Pathology in general is closely linked with clinical medi- cardiographic changes may be desired and therefore a cine and in cardiovascular pathology this interdepend- short section has been included on cutting the heart ence is, perhaps, greater than in most other specialities. according to conventionally used echocardiographic In recent years great advances in investigatory proce- planes. dures have taken place, including the examination of The heart can only react to physiological changes or fresh endomyocardial tissue obtained by bioptome, per- damage in a limited way and therefore a separate chapter mitting not only clinico-pathological correlation but also on hypertrophy and dilatation and another chapter deal- examination at histochemical and ultrastructural levels. ing with changes in the endocardium, which reflect hae- Angiography has gained wider usage and two-dimen- modynamic alteration and may additionally show sional echocardiography is no longer the preserve of diagnostic features, are also included. Degeneration to- specialized units. Percutaneous coronary transluminal gether with changes in connective tissue and ischaemic angioplasty is a relatively new approach to relieving heart disease are separately presented. Atherogenesis, obstructive coronary artery disease. Cardiac pathology recognition of myocardial infarction and the earliest mor- has therefore moved apace, providing not only a back- phological changes discernible at histochemical and ground to clinical manifestations but also visual proof for ultrastructural levels of investigation, which are within other investigations such as immunology and virology. the scope of modern routine laboratories, are empha- Such investigations have played an essential role in sized.

New techniques make it possible for investigators to examine and sometimes quantify various aspects of nuclear morphology and function; now they can derive clinically and biologically useful information about the nucleus. This book draws together a series of techniques which have been successfully applied to the study of the nucleus of tumour cells. These are of fundamental importance to researchers in tumour histopathology and medical oncology. Detailed reviews are given of various aspects of the morphology, ploidy and karyotypic status and function of the nuclei in the cells of tumours and preneoplastic lesions. Topics covered include nuclear morphology in tumour diagnosis, the ultrastructure of the nucleus, karyotypic analyses of solid tumours, flow cytometric assessment of nuclear ploidy and other parameters, histomorphometry of the nucleus, and in situ hybridisation.

This book has been written from two points of view: firstly, from the viewpoint of those who are involved in the diagnosis and treatment of lymphoid malignancies, who must meet the challenge of integrating the new biological insights into their knowledge of these diseases; and secondly, from the viewpoint of those who are involved in basic biological approaches to malignancy and immunology, who wish to know more about the function of the lymphoid tissues and their malignant diseases. Neoplasia of lymphocytes is a focus for considering many of the most important biological advances impinging on cancer in the past two or three decades, because malignant lymphoproliferative diseases offer unequalled opportunities for studying many aspects of cancer. We probably know more about lymphocytes than other normal cells because of the ease with which they can be obtained. For the same reason we probably know more about malignant lymphocytes. One or other aspect of most of the momentous advances in biology of the past two or three decades has implications for lymphoid malignancies: hybridoma technology and the use of monoclonal antibodies, gene technology, the understanding of oncogenes and growth factors in the control of growth and differentiation, insights into causation of cancer by potent tumour promoters such as the phorbol esters and by viruses, and knowledge of the control of growth function of lymphocytes themselves. Conversely, many of the advances in understanding lym phocytic leukaemias and lymphomas have implications for other cancers."

There have been many advances in the field of gastrointestinal pa thology which are of considerable clinical significance during the 13 years since the last publication of a volume of Current Topics in Pathology devoted to this subject. Many have arisen from the app lication of new techniques of histochemistry, immunocytochemi stry, quantitative morphometry and molecular and cell biology to gastrointestinal diseases, but some, notably the recognition of the association of Campylobaeter pylori with the commonest type of chronic gastritis, have been achieved using such long established 'routine' histological procedures that one wonders how their signifi cance had escaped recognition for so long. The topics covered in this volume have been selected because they present advances of relevance to the diagnostic clinical pathologist. However, they re present the personal selection of the editor, and are in no way exhaustive. Many other examples of progress in our understanding of the pathophysiology of gastrointestinal diseases have been omit ted, either because of the confines of space or because they have been well reviewed recently in other publications. Most of the workload of the practising gastrointestinal patholo gist involves the diagnosis and assessment either of inflammation or of neoplasia in the alimentary tract, and this is reflected in the topics presented in this book."

The ability to diagnose cancer by simple measurement of a serum or tissue' 'marker" has been a goal of medical science for many years. There is ample evidence that tumor cells are different from normal cells and pro duce substances that can be detected by currently available immuno chemical or biochemical methods. These "cancer markers" may be se creted proteins, enzymes, hormones, fetal serum components, monoclonal immunoglobulins, cell surface components, or cytoplasmic constituents. The purpose of this book is to present the current status of our knowledge of such cancer markers. The first tumor marker identified by laboratory means was Bence Jones protein. In a series of lectures delivered to the Royal College of Phy sicians in London in 1846, Dr. H. Bence Jones described studies on a urine sample sent to him with the following note: "Dear Dr. Jones-The tube contains urine of very high specific gravity. When boiled it becomes slightly opaque . . . . etc. " Dr. Jones found that heating of the urine after addition of nitric acid resulted in formation of a heavy precipitate; acid ad dition may have been required to bring the urine to pH 4-6 at which Bence Jones proteins are more likely to precipitate when heated. This urinary pre cipitate was associated with a bone disease termed "mollities ossium. " H. Bence Jones, Papers on Chemical Pathology, Lecture III. Lancet 2, 269-274 (1847)]."