During the past 5 years, impressive progress has been made in understanding the etiopathogenesis of expeiimental and clinical diabetes. The rapid progress that has been made in the general field of immunology has made possible new understanding regarding the role of the immune system in the pathogenesis of diabetes. The other two areas in which recent progress has been made in the field of diabetes include genetics and the role of infectious agent(s) in the etiopathogenesis of diabetes. Because of these recent developments, a vast amount of data has been accumulated and published in a number of metabolic, endocrine, immunological, and general medicine journals. The purpose of this book is to consolidate all the available information and present it in its current state. In the present volume, I strive to bring together relevant contributions from leaders in the fields of immunopathology, immunobiology, and genetics. The advancing understanding has in several instances reached the point of clinical applica tion. This volume encompasses the entire scope of modem immunology of diabetes mellitus. This volume has been divided into two major parts, Experimental Diabetes and Clinical Diabetes. In the Experimental part are included chapters dealing with the structure and functions of insulin and the immune response to insulin. Spontaneous and experimentally induced models of type I diabetes mellitus are presented. The role of virus(es) in the etiology of experimental diabetes and the influence of sex on experi mental diabetes are discussed. The transplantation of pancreas and islets is reviewed in detail."

Tumours of the prostate are the commonest types of neoplasm in the male. Whilst the benign form is virtually a universal condition in the ageing male, malignant tumours rank amongst the top causes of cancer death. Despite the fact that the involvement of the testis in the growth of the prostate has been recognised for almost two centuries, it was not until the early 1940s that Charles Huggins' studies on the effect of orchidectomy and oestrogen therapy on prostatic cancer initiated endocrine manipulation in the management of this malignancy. During the 1960s progress in the understanding of the mechanism of hormone action, achieved through advances in molecular biology and the recognition of certain aspects of hormonal control in relation to the genome, introduced a new dimension for approaching endocrine manipulation of prostatic tumours. By the end of that decade a new scientific discipline devoted to prostate research had been born, which brought together investigators in the fields of molecular biology, biochemistry, endocrinology, immunology, urology and pathology to search for the cause and to explore methods for advancing the management of abnormal prostatic growth. Since then a wealth of scientific data has accumulated on the prostate in which endocrinology has manifested itself as the cardinal aspect to which most of the findings can be related.

Diabetes is one of the oldest diseases known to mankind. It was first mentioned in the Ebers Payrus (Egypt 1500 BC) and 'honey urine' was noted by Sushrutha in India in 400 BC. By the first century of the Christian era the disease was well known, both in Roman writings and in Chinese and Japanese writings. The word 'diabetes' was first coined by the Greeks. It means a passing-through of water. They described it as a 'melting of flesh into water', meaning urine. Then in 1674 Doctor Willis discovered by heating, tasting and evaporating urine that a sweet sticky substance was in it, which, of course, was sugar. Rut sugar was not known in England in those days and honey was the only real sweet tasting substance. The Latin word 'mel' which means honey was used and the disease came to be known as diabetes mellitus - that is, the passing of honeyed urine. This is still the full name of the disease.

During the past several decades, much research effort has gone into the elucidation of the role of neuroendocrine systems as secretory and metabolic regulators of cells of a variety of organs and structures, including the testes, ovaries, adrenals, thyroid, pituitary gland, and mammary glands. However, the role of cells comprising such organs and structures in the modulation of neuroendocrine processes has received considerably less is generally less well appreciated. attention and Nonetheless, it is important that we understand the actions on neuroendocrine systems of substances that reach the brain by way of the vasculature, including hormones, cytokines, toxins, amino acids, drugs, and similar agents. In order to analyze the present state of knowledge on this topic, experimental scientists and clinicians, whose shared interests include actions of circulating agents on the brain, met at a satellite symposium of the XXXI International Congress of Physiological Sciences. This symposium, entitled Circulating Regulatory Factors and Neuroendocrine Function, was held in Smolenice Castle, Czechoslovakia, June 26-July 1, 1989, and reviews delivered at this symposium as invited presentations are published in this volume. Presentations given as free communications have been published separately and are available in Endocrinologia Experimentalis 24: 1-273, 1990.

Despite a new title, Contemporary Metabolism, Volume 1 is actually the third volume in a continuing series and succeeds The Year in Metabolism 1975- 1976 and The Year in Metabolism 1977. As in the earlier volumes, the same internationally recognized authorities review the noteworthy recent devel opments in their areas of expertise. In many instances they also address aspects that have not been considered previously. In this volume, Dr. J. Edwin Seegmiller again updates progress in understanding disorders of purine and pyrimidine metabolism. However, particular emphasis is placed on the emerging relationships with immune mechanisms. Dr. Charles S. Lieber is joined by Dr. Enrique Baraona in a continuing review of metabolic actions of ethanol. This chapter examines effects of ethanol on protein metabolism and selected features of lipid metabolism-two areas that were not included in the earlier volumes. Dr. DeWitt S. Goodman's review of disorders oflipid and lipoprotein metabo lism builds on his previous chapters, but much additional attention is directed to a critical analysis of recent advances in epidemiology and lipoprotein structures. In collaboration with Dr. Brian L. G. Morgan, Dr. Myron Winick devotes his entire chapter to a detailed review of the impact of nutrition upon brain development-an overview that has now been rendered possible by the burgeoning recent developments in this area."

I consider it an honor to have been asked to write the Foreword for The Diabetic Pancreas. Although I have been involved in the study of the pancreas since 1921, my interest goes back even further to the time, in 1918, that my father's sister, a nurse who had trained at the Massachusetts General Hospit.al, devel oped diabetes, lost weight, and died in diabetic coma. This sad event made a deep impression on me and was certainly pardy responsible for my choosing to join the Department of Physiology of the University of Toronto to begin a career in research into diabetes. This is not the place to describe in detail the wide-ranging research and study of the diabetic pancreas in which I have engaged in the past 56 years. Suffice it to say that I am familiar enough with the subject area to be able to predict a great future for this book. The editors have undertaken a very ambitious and worthwhile project, and their efforts have been supported and strengthened by contributors who are respected authorities in their fields, thus ensuring a successful presentation of this major work."

THE DISCOVERY OF INSULIN, C-PEPTIDE AND PROINSULlN, SPECIES DIFFERENCES Crude insulin was extracted and isolated from dog pancreases removed 7-1 Degrees weeks after ligation of the pancreatic duct for the first time in 1921 by Banting and Best. Its lifesaving properties were subsequently documented in pancreatectomized dogs in 1922. Only about six months elapsed from its discovery until systematic collection of calf and ox pancreases and, later, porcine pancreases was established and the blood glucose lowering effect in diabetics using the crude extract from these glands proven. It was not until 1960, however, that the primary structure of all three species of insulin, lO7 human, porcine and bovine, was elucidated . It then became evident that the differences between bovine, porcine and human insulin amounted to at mosl 3 amino acids. These apparently small differences have a significant impact on the physico-chemical characteristics of the three insulins which again affect, e.g., the rate of absorption of insulin lO9 preparations from the subcutaneous tissue and their immunogenicity, i.e.

It is curious that research in endocrinology has largely ignored the testis until quite recently. There were two impor tant reasons for this neglect; first, methods of study were difficult, and second, sperinatogenesis was considered to be the concern of the urologist or cell biologist but not the endocrinologist. Since it is now almost an ethical imperative that we develop a male contraceptive, and since a host of new techniques can be brought to bear on problems of testis function, research in male reproductive biology has effloresced. In fact, it has become possible to project aseries of workshops on the testis, each dealing with discrete aspects of biochemistry, physiology and pathology. It is fitting that this first Workshop should be on Binding and Activation, since this area is one of the frontiers in endocrinol ogy. At our present rate of progress it is probable that each of the succeeding workshops will likewise bring together leaders in a rapidly developing area. The National Institute of Child Health and Human Development has the major Federal respon sibility in reproductive biology, and has therefore agreed to sponsor this and succeeding workshops. On behalf of the Institute and for those members of the Committee who have organized this meeting, I welcome you. I am quite sure that this first Workshop on the Testis will initiate aseries of important contributions to scientific thought in male reproduc tive biology. Mortimer B. Lipsett, M. D."

The use of performance-enhancing substances by athletes is not a contemporary epi demic. In fact, athletes purportedly resorted to such measures over 2000 years ago. Even at the ancient olympic games, athletes employed special diets and concoctions to enhance their performance. In ancient Rome and ancient Egypt, gladiators and athletes ingested various potions in order to improve their physical endurance. In most in stances, such early examples of substance abuse by athletes involved relatively in nocuous chemicals, and one might presume that any enhanced performance could be attributed largely to a placebo effect. Nowadays, aside from the ethical issues, these performance-enhancing substances are far more potent and hence toxic to the body. The many performance-enhancing chemicals, drugs, and hormones exert a variety of complex pharmacological actions, but all are meant in some fashion to improve phys ical ability. Their pharmacological effects ranges from imprOVed muscle strength, as in the case of anabolic steroids and growth hormone, to central nervous system stimula tion, as in the case of caffeine or amphetamine. Analgesics or other pain-killing drugs may also be used to suppress an existing injury in order that the athlete may compete."

Paget's disease is an old disease historically, but a new disease therapeutic ally. Human remains unearthed in Lancashire, England, dating from ap proximately 900 AD, show clear evidence of the aftliction. However, it was not until the 1800s that physicians rediscovered the condition, and a little more than 100 years ago that Sir James Paget published a perceptive and accurate description of the disease from the clinical and pathologic points of view. He felt the disease represented an inflammatory condition of the skeleton and hence named it osteitis deformans. The condition again lapsed into anonymity for several decades afterwards, and therapeutic approaches did not evolve until after World War II when several groups, located mainly in the Boston area, began using a variety of agents, includ ing corticosteroids for treatment of this condition. These early attempts at therapy were unsuccessful and the condition remained essentially untreat able until the development of the calcitonins and the bisphosphonates in the 1970s. In 1978, the Paget's Disease Foundation, a private nonprofit volun tary health agency, was founded to assist individuals aftlicted by Paget's disease of bone, to provide education regarding this condition to the medical community, and to encourage research efforts to better under stand and treat the condition. An international conference was organized under the aegis of the Paget's Disease Foundation and was held in New York City in October, 1989, ten years after the founding of the Paget's Disease Foundation."

Diabetes, particularly type 2, has become increasingly more common around the world. Consequently, the effect of diabetes on the brain has achieved enormous public health importance. A surge in pre-clinical and clinical research on topics ranging from management of hyperglycemia in acute stroke to disturbances in insulin signaling in Alzheimer s disease has led to substantial progress in the field. Written by a panel of international experts, Diabetes and the Brain provides in depth reviews on the cerebral complications of diabetes, and offers introductory chapters on current insights on the pathophysiology and clinical management of diabetes, as well as neuropsychological assessment and dementia. This relevant and easily accessible book explains the cerebral complications of diabetes, with an update on diabetes for neurologists, psychiatrists, and mental health providers and researchers in general, and on stroke and dementia for those involved in research and clinical practice in diabetes."

This volume is devoted to the chemistry, immunology, molecular biology, and physiology of the human chorionic gonadotropin, heG. For this glycoprotein molecule the course from discovery to chemical deciphering covered about fifty years. It was in 1928 that Ascheim and Zondek reported that urine from pregnant women contains something that stimulates the ovaries of mice or rats. This provided the basis for the famous A-Z test for pregnancy and for the "rabbit test" modification introduced by Friedman. As researchers sought to find more sensitive responses to heG, they used a wide variety of species including the South African aquatic toad, Xenopus Zaevis, the terrestrial toad of South America, Bufo arinarus, and the African weaver finch, EupZeetes afra. The weaver finch feather reaction was particularly noteworthy, for it disclosed a non-gonadal response to heG/LH. In retrospect, this may have been an important evolutionary clue to the realization that the designation of the hormone as a "gonadotropin" may have been only partially descriptive of the molecule's physiological function--a concept that is gaining attention, as the papers in this 1980 volume divulge.

The commonest cause of blindness in young and middle-aged people in the Western world is diabetes mellitus. Although the mechanism underlying diabetic retinopathy is still not understood, the technology to reduce its progress exists, provided treatment is given at the appropriate time. Doctors caring for patients with diabetes should be familiar with all aspects of diabetic retinopathy as well as the other ocular complications of diabetes. They also need a basic knowledge of the special techniques used in the diagnosis and treatment of diabetic eye disease (fundus fluorescein angiography, retinal photocoagulation, vitrectomy) and to understand how these procedures affect the diabetic patient in terms of limitation of activities and time off work. To ensure the most efficient use of ophthalmic services a clear plan of referral to ophthalmologists is required. These are the concepts on which this guide is based, compiled by an ophthalmologist involved in the treatment of diabetic eye disease and a physician with a special interest in diabetes. In addition to doctors involved in the management of diabetic patients, this guide may be of value to ophthalmic opticians, medical students and nurses as a self-instruction manual. ' 7 1 Examination of the Eye Testing visual acuity Using the ophthalmoscope The normal fundus The abnormal fundus Recording the findings 9 TESTING VISUAL ACUITY Method Test one eye at a time. Test distant visual acuity. Correct the refractive error if the visual acuity is worse than 6/6.

It is unclear, and really no longer relevant, whether the information explosion that we now contend with has been fostered by the growth of specialization and subspecialization in medicine, or vice versa. What is clear is that the two are mutually supportive and constitute what would be in endocrine parlance a short-loop positive feedback system. As a result, for most areas of medicine, even the subspecialist in that area has a problem in maintaining currency, the more general specialist has substan tial difficulty in doing so, and the generalist is tempted to abandon the effort altogether. Nevertheless, for all, both the internal pressures of conscience and self-esteem and the external pressures generated by peer review, recertifi cation, and subspecialty boards create the need for continuous self-educa tion. We are, therefore, in an era in which the means of dissemination of new information deserves as much creative attention as does its acquisition."

When new fellows join my lab, I give them some reading materials so that they can orient themselves in their assignment in a new eld. When fellows leave my lab, some after writing their dissertations, I prefer to give them a book as a symbolic present. I was longing for a book that contained something on more or less eve- thing about the islets. At the same time, I wished it contained information as recent as possible. There are a few such books in the market but they are pretty outdated. I started picking islets myself from October 1990, when I joined the Rolf Luft Center, Karolinska Institutet. Over the years my fascination for islet research remained high. Since last year, I felt a stronger urge to do more for these mysterious and hidden mini-organs that are directly or indirectly involved in the pathogenesis of all forms of diabetes that affects ?250 million people in the world. After I launched the Islet (landesbioscience. com/journals/islets) and founded the Islet Society (isletso- ety. org), there was a momentum that could be utilized to create something equally meaningful i. e. this book. The idea cracked in September 2008. Starting September 19, 2008, I contacted an estimated 90% of the authors who published anything on the islets during 2007-2008 and who could be traced from the internet.

A. CORBIN Investigations on LHRH and its analogs have just completed their first decade. We have witnessed a veritable explosion of chemical, physiologic and pharmacologic data on this hypothalamic peptide and the approximately 1500 agonist and antagonist analogs that have been synthesized. In order to track this expanding field, I was asked to organize an international symposium on basic and clinical aspects of LHRH analogs as part of the Reproductive Health Care: CDS Symposium held in Maui, Hawaii, in October 1982. This meeting brought together a number of the leading investigators in the field. Much new state-of-the-art information was presented which I and my colleagues felt deserved a wider audience. Drs Vickery, Nestor, and Hafez consented to undertake this task. Upon review of the literature, it was apparent that there was no recent text which fully covered the breadth of developments in the field. Accordingly, the editors decided to use the symposium as a nucleus on which to build a singular, comprehensive state-of-the-art analysis of this rapidly growing discipline, and the application of such knowledge to reproductive medicine. As exemplified by the various areas of expertise provided by the individual contributors, it becomes obvious that the scope of the subject matter, while relating solely to a well-defined chemical class (LHRH analogs) and a circumscribed physiologic and pharmacologic entity (reproduction), has expanded enormously.

The actions of honnones upon systems outside of the usual target sites for such molecules represents an area of increasing interest and growing clinical significance. This volume represents a cross-section of such actions of honnones upon several relevant sites. In the first chapter of this volume Dr. Malick discusses the current status of endorphins as analgesic agents. It is now known that a more primary level of control exists for iJ-endorphin in that a 41-amino acid pep- tide has been isolated from ovine hypothalamus; this peptide stimulates iJ-endorphin release as well as the secretion of corticotropin (Vale et al. , 1981). The analgesic properties of corticotropin and its immunoactive-like analogs are well known. so it does not come as a surprise that these two classes of analgesic peptides are regulated by a common hypothalamic con- trol peptide. It may also be of interest to observe that an increase in iJ-en- dorphin concentration in the pituitary occurs in genetically obese mice and rats, and that such obesity can be attenuated through the administration of nalaxone (Margules et al. , 1978). It has also been determined that genet- ically obese mice have a probable cholecystokinin deficiency in the cerebral cortex in that this peptide is a satiety-inducing agent (Saito, et al. , 1981). The analgesic properties of the latter have also been observed. The extra-pituitary actions of another pituitary peptide, as examined in the second chapter of this volume by Dr.

More than just coincidence connects a Tate & Lyle lawsuit and artificial sweetener to Jamaican-born Chemist Bert Fraser-Reid. From his first experience of Chemistry through his diabetic father, to his determination and drive as a Chemistry student in Canada, Fraser-Reid weaves a remarkable tale integrating science, law and autobiographical anecdotes. This book arises from the lawsuit brought by Tate & Lyle against companies accused of infringing its patents for sucralose, the sweet ingredient in the artificial sweetener SPLENDA which is made by chlorinating sugar. From a 1958 undergraduate intern witnessing the pioneering experiments on sugar chlorination, to being the 1991 recipient of the world's premiere prize for carbohydrate chemistry, Fraser-Reid was groomed for his role as expert witness in the mentioned lawsuit. Nevertheless, it seems more than his career links Fraser-Reid to the case.

CHARLES Y. c. PAK Major progress has been made in the pathophysiologic elucidation and management of nephrolithiasis during the past two decades. It is now possible to detect the cause of stone disease in more than 95% of patients, to prevent recurrent formation of stones in the majority of patients, and to remove most existing stones less invasively. The assumption of editorship of this book permits me to indulge in the discussion of this progress from my personal perspective. Three somewhat fortuitous events in my academic career dictated my directing major efforts in stone research. The first event occurred in 1963 when, after having completed medical training, I was faced with two years of military service as a participant of the Berry plan. Choices were limited and disconcerting for someone interested in a research career: a staff physician at a military installation or an indian reservation, or a member of a research team in a state penitentiary. An interesting article by Norman Gershfeld on phospholi pid monolayers prompted me to write him seeking a position in his laboratory of Health (NIH) in Bethesda, MD. Partly because of at the National Institutes my rudimentary exposure and publication in surface chemistry, I was offered a position as a staff scientist and a position in the Public Health Service which satisfied the requirements of a military service."

An exciting contribution to the field, Visual Dysfunction in Diabetes: The Science of Patient Impairment and Improvement is designed with two overriding objectives: to help readers understand the impact of vision impairment in people living daily with diabetes rather than considering diabetic retinopathy solely as a medical problem, and to explore what we know and don't know about the ways diabetes affect the eye. With the plethora of new information being generated, there are still a series of fundamental questions that must be addressed if effective treatments for diabetic retinopathy are to be found and applied. Developed by a renowned group of authorities, Visual Dysfunction in Diabetes: The Science of Patient Impairment and Improvement offers responses and context for a range of questions, such as: do metabolic factors beyond glucose contribute to vision-threatening diabetic retinopathy? If so, how do these lead to vision impairment? Is diabetic retinopathy a response to systemic metabolic abnormalities or are there unique ocular problems related to insulin resistance? What is the relationship between the neural, vascular, and inflammatory abnormalities in diabetic retinopathy? Do they represent a pathological cascade induced sequentially or simultaneous responses to one or more metabolic perturbations? The authors note that if we do not address these types of questions, it is possible that the long process of developing new therapeutic s will target only one arm of the pathology and leave the retina open to damaging consequences of the others. State-of-the-art, comprehensive, and an invaluable addition the research and clinical literature, Visual Dysfunction in Diabetes: The Science of Patient Impairment and Improvement offers guidance and a significant step toward new scientific approaches that can lessen the devastating vision impairment associated with diabetes.

Early embryonic loss is a continuing social and economic global problem. In human populations the estimates of interruptions early in pregnancy range from 35-60%. In animal husbandry (swine, ruminants) fully 30% of pregnancies fail to survive early events of gestation. The futility associated with this persistant high risk is even more unsettling because of advances made in assisted reproductive technology which, although this very selective methodology has added to our knowledge of embryo-endometrial interactions, has resulted in a birth rate of only 14%. These studies have instigated comparisons of the live relative contributions of the embryo and the uterus to the outcome of pregnancy. These analyses have shown that we have learned significantly less about the role of the uterus in deciding the outcome of either natural or assisted pregnancies. In 1979 a quotation by George Corner was used to set the tone of a meeting that was devoted to discussion of the cellular and molecular aspects of implantation. In spite of the proliferation in research activity which occurred in the following 15 years our real understanding of the embryo transfer process has fallen short of our expectations. We use the Corner quotation, once again, to preface this symposium so that we may recall that the fundamental nature of the process which regulates embryo-endometrial interactions still escapes us.

Diabetes is now reaching epidemic proportions, and the associated complications of this disease can be disabling and even life-threatening. In Type 2 Diabetes: Methods and Protocols, leading investigators provide up-to-date explanations of commonly used laboratory protocols used in diabetes research. Covering the commonly described in vivo and in vitro model systems, the volume ultimately leads to an overall view of how cellular dysfunction and degeneration leads to susceptibility and diabetes disease progression. Written in the highly successful Methods in Molecular Biology series format, chapters include brief introductions to their respective subjects, lists of the necessary materials and reagents, step-by-step, readily reproducible protocols, and expert notes on troubleshooting and avoiding known pitfalls.

Comprehensive and cutting-edge, Type 2 Diabetes: Methods and Protocols offers succinct, proven techniques to aid research scientists and clinicians in continuing the study of this debilitating disease."

From the discovery of Pdx1, the first "master gene" of pancreatic development, to the most recent findings on the role of microRNAs in beta cell homeostasis, the last fifteen years have seen an unprecedented advance in our understanding of the precise development and organization of the many different cell types that make up the pancreas. It is now widely acknowledged that the therapeutic differentiation of stem cells into pancreatic cells is an ambitious endeavor that will not succeed without a thorough understanding of the molecular processes underlying the native development of the organ. This book, aimed at experts and students alike, offers a comprehensive review of the state of the art in both pancreatic development and regeneration. The many strategies to differentiate adult and embryonic stem cells into pancreatic beta cells are also discussed in the context of potential therapeutic interventions for type I diabetes.

The Fifteenth Midwest Conference on Endocrinology and Metabolism, held at the University of Missouri-Columbia on October 11 and 12th, 1979, hosted the most prominent active researchers in the world on the subject of the hormone relaxin. Each speaker presented an in-depth coverage of his chosen topic and area of expertise. Some of the data presented in this book are findings which have not been pub lished in a scientific journal. The topic of this conference is especially timely in light of the fact that this is a first confer ence devoted specifically to the hormone relaxin. Progress on this hormone has been exceedingly rapid in recent years and many signif icant breakthroughs are documented in these pages. Lively discus sions following each presentation attest to the enthusiastic research effort being pursued at the present time concerning relaxin. Traditionally the Midwest Conferences on Endocrinology and Metabolism have emphasized breadth as well as depth of coverage. The present Conference has covered the many active areas of research in relaxin, including morphological aspects of the hormone's origin, chemical purification and chemical structure, bioassays, radioimmuno assays, receptors, mechanism of biochemical action and physiological responses to the hormone. Advances in relaxin were slow since its discovery by Dr. Frederick Hisaw, Sr. in 1926 until the availability of homogenous preparations some seven years ago. In the suceeding seven years, activity in the subject has accelerated remarkably."

The conference represented by this book was made possible by support from NICHD and a planning committee headed by Dr. Richard Sherins. Two general areas of research are included: the first encompasses steroid hormone synthesis, metabolism and transport in the testis; and the second relates to hormonal regula tion of the seminiferous tubule with special emphasis on the con trol of Sertoli cell function. In addition, there are sections on the purification of unique testicular proteins and morpho logical studies with particular emphasis on the Sertoli cell. We would like to express our sincere thanks to Dr. Sherins and his staff at NICHD and to all of the people at the University of North Carolina who participated in the Conference arrangements, to Dr. Judson J. Van Wyk, Chief of the Pediatric Endocrinology Division, and Dr. H. Stanley Bennett, Director of the Laboratories for Reproductive Biology. Our very special thanks to Mrs. Carolyn Jaros for her help in handling the local arrangements. Mrs. Martha Byrd and Mrs. Linda Rollins typed the manuscripts. Miss Leslie Wells and Mr. Albert Smith kindly assisted in proof reading, and Dr. Elizabeth Wilson gave much help with the final editing process. To all of these people, we are most grateful."