Though it is a pleasure to write a short foreword to this collection of excellent scientific papers covering a range of biological topics, the rather depressing feature is the small number of papers. All-electronic publishing is developing and your Editors do have great faith in it. One problem for potential authors has been the reluctance of the abstracting journals to pay any attention to electronic journals - perhaps Springer should make a rapid move in this area and start the first all-electronic journal abstracting this type of literature. However, even the paper citation journals are starting to pay attention to the medium. The particular advantages of all-electronic publishing are beginning to emerge more clearly and it is clear that publishing video material is a unique advantage of our format. Several papers took advantage of this - for example those by Riehle and others on cell behaviour in tunnels, by Bereiter-Hahn and Voss on zonation in the plasmalemma and by Pavlikova, Zicha, Chaloupkova and Vesely on cell motility of tumour cells. These papers made essential and extensive use of video material, publishing some material of great originality. The work on cell pola rity and calcium ions in Fucus embryos by Brownlee, Manison and Anning used animation to present their results in an especially clear way. The facility of use of animation is another special advantage of our type of publication that should be more widely used."

G.P. Stamou describes the adaptive strategies that allow arthropods to cope with the severity of Mediterranean environments. After an introduction to the structure and function of Mediterranean-type ecosystems, ecophysiological adaptations to water stress and varying temperature are considered. Further, activity patterns and life cycle tactics are discussed in relation to the peculiarity of Mediterranean environments. Phenological patterns and population dynamics as well as community structures are also presented. The volume ends with a synthesis of life history tactics.

The fifth Oxford Conference was held on September 17th-19th, 1991, at the Fuji Institute of Training in Japan -the first time that the meeting has taken place in the Asian area. The facts that only a relatively few Japanese had attended previous Oxford Conferences and that Japan is far from other regions with possible participants made the organizers anticipate a small attendance at the meeting. However, contrary to our expectations, 198 active members (72 foreign and 126 domestic participants) submitted 146 papers from 15 countries. This was far beyond our preliminary estimate and could have caused problems in providing accommodation for the participants and in programming their scientific presentations. These difficulties, however, were successfully overcome by using nearby hotels, by telecasting presentations into a second lecture room and by displaying a substantial number of poster presentations during the whole period of the meeting. The meeting had two types of sessions: regular and current topics. The first paper in each session represented a shon overview or introduction so as to make it easier for the audience to comprehend the problems at issue. Because of the large number of papers submitted, carefully selected speakers (mostly well-known scholars) made excellent presentations that were followed by lively discussions. In this way, the conference laid a foundation on which to base its continued scientific success.

The Henry Goldberg Workshops were set up to address the following goals: (1) To foster interdisciplinary interaction between scientists and cardiologists, identify missing links, and catalyze new ideas. (2) To relate basic microscale phenomena to the global, clinically manifested cardiac function. (3) To relate conceptual modeling and quantitative analysis to experimental and clinical data. (4) To encourage international cooperation so as to disperse medical and technological knowhow and lead to better understanding of the cardiac system. The first Henry Goldberg Workshop, held in Haifa in 1984, introduced the concept of interaction between cardiac mechanics, electrical activation, perfusion, and metabolism, emphasizing imaging in the clinical environment. The second Workshop, in 1985, discussed the same parameters with a slant towards the control aspects. The third Goldberg Workshop, held in the USA at Rutgers University in 1986, highlighted the transformation of the microscale activation phenomena to macroscale activity and performance, relating electrophysiology, energy metabolism, and cardiac mechanics. The fourth Goldberg Workshop, in 1987, continued the effort to elucidate the interactions among the various parameters affecting cardiac performance, with emphasis on the ischemic heart. The fifth Workshop, held in Cambridge, UK, in 1988, dwelt on the effects of inhomogeneity of the cardiac muscle on its performance in health and disease. The sixth Workshop highlighted the role of new modem imaging techniques, that allow us to gain more insight into local and global cardiac performance in cardiac research and clinical practice.

The International Societyon Oxygen Transport to Tissue (ISOTT) was founded in 1973 "to facilitate the exchange of scientific information among those interested in any aspect of the transport and/or utilization of oxygen in tissues." Its members span virtually all disciplines, extending from various branches of clinical medicine such as anesthesiology, ophthalmology and surgery through the basic medical sciences of physiology and biochemistry to most branches ofthe physical sciences and engineering. The eighteenth annual meeting of ISOTT was held in 1990 for four days, from July 19 to 22, in the Sheraton Hotel in Townsville, Queensland, Australia. The usual ISOTT format, which was originated in 1985 by Dr. Ian Longmuir, was continued. Almost all presentations were posters with an accompanying, scheduled, brief, slide presentation and discussion. All posters remained in place for the entire four days of the meeting. There were no simultaneous sessions. Essentially all aspects of physiological transport were covered at this meeting with possibly somewhat more emphasis on methods and instrumentation. The editors gratefully acknowledge the photographic skills of Dr. Jens Hoper who took the group picture during the outing to Magnetic Island on July 21. We are also most grateful to Dr. Rod D. Braun of Evanston for his invaluable editorial assistance. This volume is the thirteenth in the Plenum series Oxygen Transport to Tissue.

During the past decade interest in the formation of complex disorderly patterns far from equilibrium has grown rapidly. This interest has been stim ulated by the development of new approaches (based primarily on fractal geometry) to the quantitative description of complex structures, increased understanding of non-linear phenomena and the introduction of a variety of models (such as the diffusion-limited aggregation model) that provide paradigms for non-equilibrium growth phenomena. Advances in computer technology have played a crucial role in both the experimental and theoret ical aspects of this enterprise. Substantial progress has been made towards the development of comprehensive understanding of non-equilibrium growth phenomena but most of our current understanding is based on simple com puter models. Pattern formation processes are important in almost all areas of science and technology, and, clearly, pattern growth pervades biology. Very often remarkably similar patterns are found in quite diverse systems. In some case (dielectric breakdown, electrodeposition, fluid-fluid displacement in porous media, dissolution patterns and random dendritic growth for example) the underlying causes of this similarity is quite well understood. In other cases (vascular trees, nerve cells and river networks for example) we do not yet know if a fundamental relationship exists between the mechanisms leading the formation of these structures.

Ecology is characterized by a rapidly growing complexity and diversity of facts, aspects, examples, and observations. What is badly needed is the development of common patterns, of rules that, as in other sciences such as physics, can more generally explain the increasing complexity and variability we observe. Tom White, being one of the "seniors" in ecology, makes such an attempt in his book. the pattern he shows and explains with numerous examples from the entire animal kingdom is a universal hunger for nitrogen, a misery that drives the ecology of all organisms. He advocates that the awareness of this fundamental role that the limitation of nitrogen plays in the ecology of all organisms should be as a much part of each ecologis's intellectual equipment as is the awareness of the fact of evolution by means of natural selection. His claim is that not "enery" but "nitrogen" is the most limited "currency" in the animal world for the production and growth of their young.

Similarities in structure and function between pigs and human beings include size, feeding patterns, digestive physiology, dietary habits, kidney structure and function, pulmo nary vascular bed structure, coronary artery distribution, propensity to obesity, respiratory rates, tidal volumes and social behaviors. Since the pig is an omnivore, it provides an adaptable model to evaluate chronic and acute exposures to xenobiotics such as alcohoL caffeine, tobacco, food additives and environmental pollutants. Swine have been used successfully as models to evaluate alcoholism, diabetes, absorption, digestion, total paren teral nutrition, organ transplantation, atherosclerosis, exercise, hypertension. hemorrhagic hypotension, melanoma, gingivitis, obstructive and reflux nephropathy. osteochondrosis. dermal healing and septic shock. A severe and worsening shortage of organs and tissues for transplantation in patients with severe organ failure has encouraged the consideration of inter species or xenotransplan tation. In developing programs toward this end, the pig generally is viewed as the preferred donor because of its size, physiology and availability. The pig harbors relatively few diseases which could be transmitted inadvertently to human patients. The ability to genetically modify swine to ameliorate the consequences of the human immune response offers a further significant advantage. Another important consideration for an animal model is that basic biologic back ground information be available for investigators to design future prospective studies."

The aimoftheHypospadiasand Genital Symposium, held at theUniversityof California,SanFrancisco,wastoprovideaforumforauthoritativeinvestigatorswhoare activelyinvolvedinthevariousdisciplineswhichdefinetheleadingedgesofhypospadias and genital research. It is important for such investigators to continue to meet for the purpose of discussing the latest developments in their individual fields, to analyze the significanceofcurrent research, to discuss new tactics for unresolved problems and to develop new theories andapproaches asneeded. The two day conference on hypospadiasandgenitaldevelopment research was organizedintothreesections: 1)HumanStudies;2)MechanismofGenitalDevelopment; and 3) Endocrine Disruptors and Sexual Dimorphism in the Animal Kingdom. Each sessionwasintroducedbyanexpertmoderatorfollowedtheinvitedspeakerswithtimefor extensiveinteractionbetweeninvestigators. Thisbookdocumentstheproceedingsofthe HypospadiasandGenitalDevelopmentSymposium. Iwould especially like to thank Kari Gaudette for editorial assistants, Cynthia Ashe, Selcuk Yucel, Antonio Souza and the administrative staffinthe Departmentof Urology. Ihopeyoufindthisresourceuseful. Laurence S. Baskin,M. D. ProgramChair ChiefPediatricUrology UCSF vii ACKNOWLEDGEMENTS Supportforthissymposiumisgratefullyacknowledged TheNationalInstituteofHealthGrant#R13DK*HDS997 UCSFDepartmentofUrology AmericanUrologicAssociation CONTENTS Introduction...1 SECTIONI. HUMANSTUDIES EpidemiologyofHypospadias...*...*...25 J. DavidErickson EndocrineEvaluationofHypospadias...31 G. HyunandT. Kolon EndocrineAbnormalitiesinBoyswithHypospadias...45 R. I. Silver GeneticandClinicalStudiesonHypospadias...***...**...*...73 A. Nordenskjold SECTIONII. MECHANISMOFGENITALDEVELOPMENT DevelopmentofthePenileUrethra. . 87 G. CunhaandL. Baskin AnatomicalStudiesoftheMouseGenitalTubercle...103 L. Baskin,W. Liu,J. Bastacky,andS. Yucel AnatomicalStudiesoftheFibroblastGrowthFactor-l0Mutant,Sonic HedgeHogMutant,andAndrogenReceptorMutantMouseGenital Tubercle...*. **. . 123 S. Yllcel,W. Liu,DCordero,A. Donjacour,G. Cunha,andL. Baskin DevelopmentalGeneticsofHypospadias...149 M. Cohn xiii xiv Contents DevelopmentoftheMouseExternalGenitalia: UniqueModelof Organogenesis...159 K. Suzuki, K. Shiota,Y. Zhang,L. Lei,andG. Yamada NewConceptsontheDevelopmentoCtheVagina...173 E. Shapiro. H. Huang,andX. R. Wu SECTIONIII. ENDOCRINEDISRUPTORSANDSEXUAL DIMORPHISMINTHEANIMALKINGDOM EndocrineDisruptionOverview: AreMalesatRisk? 189 T. Colburn EndocrineDisruptionandHypospadias...203 G. Steinhardt Toxicant-InducedHypospadiasintheMaleRat * 217 L. E. Gray. . I. Ostby,J. Fun,C. Wolf,C. Lambright,V. Wilson, and N. Noreiga MasculinizationofFemaleMammals: LessonsfromNature...243 N. J. PI:H'candS. Glickman Index...255 SectionI Introduction HYPOSPADIAS LaurenceS. Baskin* M. D. ,FAAP 1.

Introduction to Mammalian Reproduction is a welcome contribution to the fields of gametogenesis, gamete transport, fertilization, and reproduction technologies. Key topics covered include:
*formation and maturation of male gametes;
*morphology and physiology of female gametes;
*how the sperm meets the egg;
*sperm-egg fusion, egg activation, and implantation of fertilized egg;
*assisted reproduction and environmental chemicals that have an effect on formation and function of male and female gametes. This book is for both researchers and students involved in reproductive biology.

Discovery of the mechanism for V(D)J hypermutation remains a basic goal of immunology despite the best efforts of many labo ratories. The existence of catalyzed, site-specific mutation and its exploitation for the somatic evolution of lymphocytes are re markable adaptations, yet since the discovery of hypermutation in 1970 (see cover), much hard work has generated little. Indeed, our knowledge of what is probably absolutely required for the mutator's action can be succinctly expressed: /g gene enhancers. Table 1 of Winter et a .'s chapter puts into a historical perspec tive how our notions of the mutator have changed over the years. Despite these modest gains, most of us feel that this is the best of times. Our work has not only shown us what the mutator is not, it has also, like an artist's preliminary sketch, defined the questions and experiments we must face without diminishing the potential for new biology. In short, it is great fun to toil against a significant and enigmatic problem."

The field of olfactory research and chemical communication is in the early stages of revolutionary change, and many aspects of this revolution are reflected in the chapters in this book. Thus, it should serve admirably as an up-to-date reference. First, a wide range of vertebrate groups and species are represented. Second, there are excellent reviews of specific topics and theoretical approaches to communication by odors, including chapters on signal specialization and evolution in mammals, the evolution of hormonal pheromones in fish, alarm pheromones in fish, chemical repellents, the chemical signals involved in endocrine responses in mice, and the controversy over human pheromones. Third, there are exciting new findings presented in numerous specific topic areas, such as the chemis try of pheromones in a wide range of species (salamanders to elephants), the chemistry of proteins that control the release of pheromones, the molecular biology and physiology of detection, coding and response to odor signals, the effects of experience on sensitivity to odors, the role of genes of the immune system in odor production and in human mate choice, the function and perception of scent over-marks, the recognition of individuals and kin by odors, the influence of odors on predator-prey interactions, and the use of odors to help control pests. This book is an offshoot of the Eighth International Symposium on Chemical Sig nals in Vertebrates, held at Cornell University in Ithaca, New York, July 20-25, 1997, hosted and organized by Bob Johnston.

It has been great fun to write this book, even though it has taken longer than planned, and occasionally been exasperating. The most difficult problem was deciding what to exclude among so many interesting things, because the available material usually exceeded the space. Because a book like this covers so many aspects, each component must be limited. This book is intended for graduate and undergraduate students as well as professional scientists who want to work with animal flight or to gain some insight into flight mechanics, aerodynamics, energetics, physiology, morpho logy, ecology and evolution. My aim has not been to give the whole mathe matical explanation of flight, but to provide an outline and summary of the main theories for the understanding of how aerofoils respond to an airflow. I also hope to give the reader some insight into how flight morphology and the various wing shapes have evolved and are adapted to different ecological niches and habitats."

The research field of somatosensory processing in mammals has experienced revolutionary changes in recent years. Accumulation of basic and clinical data has greatly accelerated, and new phenomena have emerged. With the aid of new, refined methods, molecular and cellular changes have been described, underlying the signal transduction-transmission between the internal/external environment and the central nervous system have been described. The discovery of the interaction between the nervous and the immune system has, for example changed our view on the development of inflammatory diseases, while the cloning of genes encoding different trophic factors has boosted studies revealing profound changes in the regeneration of neurons, and induction of changes in phenotype. The study of the pre-and postsynaptic modulation of transmitter release, and the examination of the combined effects of amino acid and peptide transmitters has become recently possible by using cultured cell lines and in vitro techniques. Although it is in embryonic state, computational properties of single DRG cells under normal and pathological conditions are being investigated. Results soon or later will have a great impact on pain research and consequently ultimately in clinical pain management. This brief introduction indicates how our knowledge of the somatosensory system has increased dramatically recently. However, many investigators cultivate only a very specific field in the growing area of somatosensory research and find it difficult to integrate a more universal knowledge of their work.

How do hormones and growth factors regulate animal growth in the developing embryo and after injury? What processes at the molecular level determine the growth patterns of different tissues? In this diverse synthesis of recent research the regulation of growth in response to environmental and genetic stimuli is discussed at the level of the animal, tissues and cells. Contrasts are drawn between regulation in foetal and adult tissues, and in different tissues such as the CNS, bone and muscle. Functional chapters focus on the molecular links between mechanical tension and muscle growth, for example, while other chapters review the roles of specific molecules such as growth hormone. This state-of-the-art review will be of significant interest to graduate students and research scientists in the fields of animal growth, endocrinology and cell biology.

Space missions subject human beings or any other target of a spacecraft to a radiation environment of an intensity and composition not available on earth. Whereas for missions in low earth orbit (LEO), such as those using the Space Shuttle or Space Station scenario, radiation exposure guidelines have been developed and have been adopted by spacefaring agencies, for exploratory class missions that will take the space travellers outside the protective confines of the geomagnetic field sufficient guidelines for radiation protection are still outstanding. For a piloted Mars mission, the whole concept of radiation protection needs to be reconsidered. Since there is an increasing interest ci many nations and space agencies in establishing a lunar base and lor exploring Mars by manned missions, it is both, timely and important to develop appropriate risk estimates and radiation protection guidelines which will have an influence on the design and structure of space vehicles and habitation areas of the extraterrestrial settlements. This book is the result of a multidisciplinary effort to assess the state of art in our knowledge on the radiation situation during deep space missions and on the impact of this complex radiation environment on the space traveller. ]t comprises the lectures by the faculty members as well as short contributions by the students given at the NATO Advanced Study Institute "Biological Effects and Physics of Solar and Galactic Cosmic Radiation" held in Armacao de Pera, Portugal, 12-23 October, 1991.

First published in 1981, this book presents an original approach to an area of great importance in comparative zoology and physiology and evolutionary biology: the evolution of air breathing in vertebrates from aquatic ancestors. The subject is approached from a functional as well as an anatomical viewpoint, utilising knowledge of the physiology of extant animals to trace probable evolutionary steps. Opening with a brief summary of current views of vertebrate evolution, the authors then go on to deal with problems of oxygen transfer in water and air and the structure and function of gills and lungs. Carbon dioxide transfer in water-breathing forms is seen as being tightly coupled to an ion and acid-base regulation. The evolution of air breathing is seen as a several-stage process, beginning with the evolution of accessory air-breathing structures for oxygen uptake.

The aim of the authors in writing this monograph has been to provide a comprehensive and critical, but personal account of salt glands. Papers on salt glands are scattered through a great many different journals. There is therefore a great need for a synthesis of what is known about salt glands. The means by which salt glands perform their vital function of forming and excreting a concentrated salt solution is of great biological importance in understanding salt and water relations in the cells of all living things. In addition to the basic physiology of salt glands there is consideration of their ecological importance, their interaction with other systems of the body, their role in non-marine birds and reptiles and their evolution. Salt glands have interested biologists from a wide range of disciplines. This book brings together the scattered literature and will be a convenient source of reference to those working in the field, as well as providing information for comparative studies and for teaching purposes.

Comparative Physiology: Primitive Mammals attempts to dispel the widely held notion that 'primitive' animals are less advanced or less complex than the 'non-primitive'. The term 'primitive', or more accurately 'conservative', refers to the fact that these animals have retained many of the characteristics of their evolutionary ancestors. Because they have been able to adapt to a variety of environmental conditions, these so-called primitive animals should be considered highly successful evolutionary solutions. The papers contained in this volume are the result of the Fourth International Conference on Comparative Physiology held at Crans-sur-Sierre in 1978. The conference, which was sponsored by the Interunion Commission on Comparative Physiology representing the International Unions of Biological Sciences, Physiological Sciences, and Pure and Applied Biophysics, brought together scientists from various fields to discuss the widely scattered information on primitive mammals from the perspective of comparative physiology.

A number of remarkable recent breakthroughs have made the study of nitric oxide one of the most exciting fields in physiology and pathophysiology. This authoritative edited volume reviews the progress to date and opens perspectives to novel diagnostic and therapeutic strategies. The contributors are leading authorites, in most cases the investigators who have pioneered the ideas explored in the book.

The past two decades have witnessed an unprecedented growth in the field ofneuroendocrinology. The conjoint research contributions by clinicians and basic scientists have promulgated revolutionary concepts at a breakneck speed. This first volume in Clinical Surveys in Endocrinology, The Pituitary Gland, has been written with but one purpose in mind: to integrate the current knowledge in this dynamic field with the existing body of information already available to the clinician. The chapters in this book attempt to portray current research information seen through the eyes of a clinician. The contributions of pioneers in each field have been placed in a perspective relevant to the practicing endocrinologist. The selection of the almost 1500 references from a bewil of literature has been inftuenced by the degree to which these dering body articles-original as weil as review papers-contributed to the growth of pi tuitary endocrinology. Despite the most scrutinizing attempts, it is inevitable and regrettable that works of importance must be excluded due to the practical limitations of any comprehensive work. Nevertheless, to the researcher these references are complete enough to serve as a significant resource. To the reader who wishes to gain an indepth clinical perspective of pituitary disor ders, this work is written precisely from that vantage point. The single authorship of this work notwithstanding, several friends have been instrumental in the completion of this work. I deeply appreciate the incessant zeal and excellent assistance of Ms."

I had the good fortune to first meet Gerald Kuchling in 1985 when attending a conference held at the CNRS research centre, the Centre d'Etudes Biologiques des Animaux Sauvages (CEBAS), which is a wonderful scientific field station tucked away in the Foret de Chize, not far from the southwest town of Niort in France. The topic of the meeting, which included many invited overseas scientists, was "Physiological Regulations as Adaptive Mechanisms", and it was superbly organised by Ivan Assenmacher and Jean Boissin who together edited the impor- tant volume of papers published from the meeting. My stay in Chize was, unfor- tunately, cut short as the wife of a very close colleague died on the night of the first day of the meeting and I had to return to Paris to assist with the funeral -but not before I had the chance to meet and talk with Gerald. He was presenting some of his work on a terrestrial tortoise (or turtle depending upon one's origins) - Testudo hermanni - a species that is now extremely rare in France but still relatively abundant in the then Yugoslavia. Gerald had been working in Yugoslavia, collecting blood samples from both males and females in an attempt to decipher details of its reproductive biology.

This book is a compendium of proceedings from the Symposium on Growth Hormone II: Basic and Clinical Aspects. The intent of the sym posium was to review current aspects of the rapidly expanding science of growth hormone (GH) neuroendocrinology, especially those develop ments that occurred since our last meeting in 1985. The meeting was timely since there have been many new and exciting developments in basic research on the GH axis, and several new clinical applications for GH other than growth have been identified. For example, significant strides have been made into use of the bioengineered hormone as an anabolic in debilitated states and as an immunorestorative agent. Both these areas have received most attention as they relate to geriatric popu lations. Furthermore, recent focus on a novel family of GH secretagogues that complement the action of GHRH has shown that in animal models, these compounds have the potential to restore GH secretion in deficient or insufficient states, including growth retardation, obesity, and aging. Accordingly, these xenobiotics may have significant potential as drug products to stimulate physiological GH secretion and, thus, resist or reverse some of the maladaptive changes in form and function resulting from GH insufficiency. The importance of these agents as drug candidates is underscored by the diversity of molecules that have been studied by various pharmaceutical companies and the recent discovery that non peptide analogs with high oral bioavailability can be synthesized."

The auditory system has a remarkable ability to adjust to an ever-changing environment. The six review chapters that comprise Plasticity of the Central Auditory System cover a spectrum of issues concerning this ability to adapt, defined by the widely applicable term "plasticity." With chapters focusing on the development of the cochlear nucleus, the mammalian superior olivary complex, plasticity in binaural hearing, plasticity in the auditory cortex, neural plasticity in bird songs, and plasticity in the insect auditory system, this volume represents much of the most current research in this field. The volume is thorough enough to stand alone, but is closely related a previous SHAR volume, Development of the Auditory System (Volume 9) by Rubel, Popper, and Fay. The book fully addresses the difficulties, challenges, and complexities of this topic as it applies to the auditory development of a wide variety of species.

This volume, The Adrenal Gland, is the second in the Clinical Surveys in Endo crinology series. Like its predecessor on the pituitary gland, this work is written with one purpose in mind-to view the vast, relevant adrenal literature through a clinician's eyes. The intricate, and often complex, interrelationship between the clinical and research perspectives of "adrenology" poses a challenge. This is, in part, due to the commonly held belief that the milieux of steroid hormone research and clinical medicine are parallel phenomena, not destined to meet. But the twain do meet, and often with relative ease, when viewed as twin facets of the same gem. The view presented in this work is from the vantage point of the clinical endocrinologist who applies the research literature to understand adre nal diseases more clearly. Adrenal pathology is arguably the most fascinating of all endocrinopathies. The images of patients suffering from adrenal diseases are of kaleidoscopic quality: the newborn child with ambiguous genitalia, in whom the very first ritual of assigning sex becomes shrouded with uncertainty; the revitalized pa tient with hitherto undiagnosed Addison's disease, who but for the cognitive powers of the endocrinologist would have ultimately succumbed, undiagnosed; the virilized female with adrenal tumor and its attendant onslaught on the body and mind; the febrile patient with pheochromocytoma masquerading as fever of undetermined origin for months."