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Tissue damage triggers a rapid and robust inflammatory response in order to clear and repair a wound. Remarkably, many of the cell biology features that underlie the ability of leukocytes to home in to sites of injury and to fight infection-most of which are topics of intensive current research-were originally observed in various weird and wonderful translucent organisms over a century ago by Elie Metchnikoff, the "father of innate immunity," who is credited with discovering phagocytes in 1882. In this review, we use Metchnikoff's seminal lectures as a starting point to discuss the tremendous variety of cell biology features that underpin the function of these multitasking immune cells. Some of these are shared by other cell types (including aspects of motility, membrane trafficking, cell division, and death), but others are more unique features of innate immune cells, enabling them to fulfill their specialized functions, such as encapsulation of invading pathogens, cell-cell fusion in response to foreign bodies, and their self-sacrifice as occurs during NETosis., (© 2020 Weavers and Martin.)

Introduction : 'Chronic inflammatory immune-related skin disease' (ISDs) is an umbrella term grouping together heterogeneous entities characterized by chronic inflammation potentially involving the whole skin. We are not covering all ISDs in this review, but take a few as the most representative, including nonbullous and bullous diseases. The question we are aiming to address can be summarized as follows: 'despite the differences, is it possible to define some unifying epidemiologic characteristics and shared progression pathways which can guide the organization of healthcare?' Areas covered : This review covers incidence, prevalence, risk factors and prognosis of psoriasis, atopic dermatitis (AD), pemphigus and pemphigoid. Medline, Embase and the Cochrane Library were searched for papers published between January 2005 and December 2019. Expert opinion : ISDs epidemiology varies according to the ISD type, age, sex, climate, and sociodemographic variables. AD and psoriasis pose a considerable public health burden owing to their high prevalence worldwide and morbidity. Their secular trend of increasing incidence points to a role for environmental factors and gene-environment interactions. Bullous diseases are much rarer, with limited data available. Worldwide, the leading cause of skin disease disability-adjusted life-years (DALYs) is attributable to AD. Future research should focus on risk factors and prevention at the global level.

Neuroimmunology as a separate discipline has its roots in the fields of neurology, neuroscience and immunology. Early studies of the brain by Golgi and Cajal, the detailed clinical and neuropathology studies of Charcot and Thompson's seminal paper on graft acceptance in the central nervous system, kindled a now rapidly expanding research area, with the aim of understanding pathological mechanisms of inflammatory components of neurological disorders. While neuroimmunologists originally focused on classical neuroinflammatory disorders, such as multiple sclerosis and infections, there is strong evidence to suggest that the immune response contributes to genetic white matter disorders, epilepsy, neurodegenerative diseases, neuropsychiatric disorders, peripheral nervous system and neuro-oncological conditions, as well as ageing. Technological advances have greatly aided our knowledge of how the immune system influences the nervous system during development and ageing, and how such responses contribute to disease as well as regeneration and repair. Here, we highlight historical aspects and milestones in the field of neuroimmunology and discuss the paradigm shifts that have helped provide novel insights into disease mechanisms. We propose future perspectives including molecular biological studies and experimental models that may have the potential to push many areas of neuroimmunology. Such an understanding of neuroimmunology will open up new avenues for therapeutic approaches to manipulate neuroinflammation., (© 2019 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.)

This study examines case reports of brain diseases attributed to inflammation in Richard Bright's Reports of Medical Cases, Volume II. The rationale for the belief that these cases were due to inflammation is discussed in light of theories of inflammation that were current in Bright's time. The consequences of these theories for the therapy of brain diseases are evaluated. The value of Bright's reports lies in the accuracy of the descriptions of a number of brain diseases, featuring descriptions of symptoms or conditions that were novel or not well known in the early nineteenth century. They provided a conception of diseases that constituted "typical condition of many patients," rather than "disorderly condition of a particular patient." Many cases are illustrated by remarkable images of pathological specimens.

There is increasing scientific and clinical interest in elucidating the biology of type I Interferons, which began approximately 60 years ago with the concept of "viral interference", a property that reduces the ability of a virus to infect cells. Although our understanding of the multiple cellular and molecular functions of interferons has advanced significantly, much remains to be learned and type I Interferons remain an active and fascinating area of inquiry. In this review, we cover some general aspects of type I interferon genes, with emphasis on interferon-alpha, and various aspects of molecular mechanisms triggered by type I interferons and toll-like receptor signaling by the Janus activated kinase/signal transducer activation of transcription (JAK-STAT) pathway and interferon regulatory factor pathway. We will also describe the role of type I interferons in autoimmune and inflammatory diseases, and its potential use as therapeutic agent., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Hans Selye made a great impact on the Hungarian medical, scientific and public life. His first Hungarian publication about the alarm-reaction appeared 1938 in the Orvosi Hetilap. His Hungarian relationship was quite extensive after the war as he published, gave lectures, and accepted Hungarian students for specialized training in his Canadian institute saw. The rich documents in archives about Selye are currently being processed and those will surely shed light on Selye's life in further details.

Use of matierials of animal or human origin in dentistry (and generally in medicine) these days is regarded as an unusal way of intervention. However in earlier times, different tissues, parts, products and organs of animals were frequently used in healing. Some of these methods were rooted in magical thinking. As analogical treatments--based on similarity or analogy--e.g. powder of horn or teeth of pike was used for the treatment of decayed teeth and different worms, maggots, veenies were applied against "toothworm". By difficult eruption of primary teeth bone marrow or brain mixed with cockridge-blood and goatmilk was a widely used medicine. Butter and honey were able to help the growing of teeth, as well. Parts of frog (fe: flippers) were also components of curing materials. Egg as the symbol of life was often an ingredient of medicaments. For the treatment of inflamed gum different animal materials were used, like chin and teeth of wolf, pike, crayfish, milk, honey, human saliva etc. Animal or human stools, mucks (containing enzymes) did one's bit in healing of oral and dental illnesses and were applied as fomentation or swathing. Placing a leech on the inflamed face was a common procedure in the past even as the use of earwax in lipnook. In our days tissues, parts or products of animals (or human beings) usually never allowed to get into contact with the body of patients. It's a much safer routine, at the same time however a precious traditional knowledge vanishes forever.

From the first reliable descriptions of acne in the early 19th century, dermatologists recognized it as a disease of the pilosebaceous follicle. Until the middle of the 20th century, they hypothesized that seborrhoea, follicular keratosis and microorganisms could be individually responsible for the acne lesions. Inflammation was only regarded as the final and inescapable step of the acne process. Although the importance of these factors has been reevaluated, recent works still regarded them as mandatory. In the 1970s, the onset of isotretinoin dramatically improved acne management. It also provided great opportunities for a better understanding of the pathogenic factors of acne. This study analyzes their genesis and development from the seminal contributions until recent advances.

Type 2 diabetes mellitus (T2DM) is increasingly common worldwide. Related complications account for increased morbidity and mortality, and enormous healthcare spending. Knowledge of the pathophysiological derangements involved in the occurrence of diabetes and related complications is critical for successful prevention and control solutions. Epidemiologic studies have established an association between inflammatory biomarkers and the occurrence of T2DM and complications. Adipose tissue appears to be a major site of production of those inflammatory biomarkers, as a result of the cross-talk between adipose cells, macrophages, and other immune cells that infiltrate the expanding adipose tissue. The triggering mechanisms of the inflammation in T2DM are still ill-understood. Inflammatory response likely contributes to T2DM occurrence by causing insulin resistance, and is in turn intensified in the presence of hyperglycemia to promote long-term complications of diabetes. Targeting inflammatory pathways could possibly be a component of the strategies to prevent and control diabetes and related complications.

The Center for Human Immunology, Autoimmunity, and Inflammation (CHI) is an exciting initiative of the NIH intramural program begun in 2009. It is uniquely trans-NIH in support (multiple institutes) and leadership (senior scientists from several institutes who donate their time). Its goal is an in-depth assessment of the human immune system using high-throughput multiplex technologies for examination of immune cells and their products, the genome, gene expression, and epigenetic modulation obtained from individuals both before and after interventions, adding information from in-depth clinical phenotyping, and then applying advanced biostatistical and computer modeling methods for mining these diverse data. The aim is to develop a comprehensive picture of the human "immunome" in health and disease, elucidate common pathogenic pathways in various diseases, identify and validate biomarkers that predict disease progression and responses to new interventions, and identify potential targets for new therapeutic modalities. Challenges, opportunities, and progress are detailed., (Published 2013. This article is a U.S. Government work and is in the public domain in the USA.)

Introduction: Historical overview of development investigations on inflammation in Russia up to date is presented., Material and Methods: Analysis of modern Russian language literature (1950-2010) on history of medicine and researchers' activity on inflammation, as well as Russian language content of internet on this theme, was made. Many names of Russian researchers are still little known to the English-speaking Western readers., Results: Starting in the eighteenth century, the mystery of the inner workings of the inflammation process attracted the interest of physicians and biologists of the Russian Empire. Accumulated knowledge focused mainly on the etiological factors of inflammation. In the nineteenth century, scientific schools emerged for studying inflammation and established close contacts with leading scientists in other countries. At this time, Ilya Mechnikov formulated his famous biological theory of inflammation, according to which inflammation is a protective adaptation response to an injury. He also developed his teaching on phagocytosis and was awarded the Nobel Prize. In the twentieth century, Russian scientists participated in the discovery of viruses and new bacterial pathogens, and in the investigation of the mechanics of the genesis and development of inflammatory processes., Conclusion: Today interest in studies of inflammation in Russia is on the increase; scientists united by the Russian Inflammation Society continue their quest to investigate inflammatory mediators, and study molecular and cellular mechanisms and approaches in the treatment of complications associated with inflammation.

Sepsis is among the leading causes of death worldwide and its incidence is increasing. Defined as the host response to infection, sepsis is a clinical syndrome considered to be the expression of a dysregulated immune reaction induced by danger signals that may lead to organ failure and death. Remarkable progresses have been made in our understanding of the molecular basis of host defenses in recent years. The host defense response is initiated by innate immune sensors of danger signals designated under the collective name of pattern-recognition receptors. Members of the family of microbial sensors include the complement system, the Toll-like receptors, the nucleotide-binding oligomerization domainlike receptors, the RIG-I-like helicases and the C-type lectin receptors. Ligand-activated pattern-recognition receptors kick off a cascade of intracellular events resulting in the expression of co-stimulatory molecules and release of effector molecules playing a fundamental role in the initiation of the innate and adaptive immune responses. Fine tuning of proinflammatory and anti-inflammatory reactions is critical for keeping the innate immune response in check. Overwhelming or dysregulated responses induced by infectious stimuli may have dramatic consequences for the host as shown by the profound derangements observed in sepsis. Unfortunately, translational research approaches aimed at the development of therapies targeting newly identified innate immune pathways have not held their promises. Indeed, all recent clinical investigations of adjunctive anti-sepsis treatments had little, if any, impact on morbidity and all-cause mortality of sepsis. Dissecting the mechanisms underlying the transition from infection to sepsis is essential for solving the sepsis enigma. Important components of the puzzle have already been identified, but the hunt must go on in the laboratory and at the bedside.

Hans Selye's single author short letter to Nature (1936, 138(3479):32) inspired a huge and still growing wave of medical research. His experiments with rats led to recognition of the "general adaptation syndrome", later renamed by Selye "stress response": the triad of enlarged adrenal glands, lymph node and thymic atrophy, and gastric erosions/ulcers. Because of the major role of glucocorticoids (named by Selye), he performed extensive structure-activity studies in the 1930s-1940s, resulting in the first rational classification of steroid hormones, e.g. corticoids, testoids/androgens, and folliculoids/estrogens. During those years, he recognized the respective anti- and pro-inflammatory actions of gluco- and mineralocorticoids in animal models, several years before demonstration of anti-rheumatic actions of cortisone and adrenocorticotrophic hormones in patients. Nevertheless, Selye did not receive a Nobel Prize, which was awarded in 1950 to the clinician Hench and the two chemists who isolated and synthesized some of the glucocorticoids. Nonetheless, Selye was internationally recognized as a world authority in endocrinology, steroid chemistry, experimental surgery, and pathology. He wrote over 1500 original and review articles, singly authored 32 books, and trained 40 PhD students, one of whom (Roger Guillemin) won a Nobel Prize for isolating the hypothalamic releasing factors/hormones. Here, we consider the main implications of his first article launching the biological stress concept and the key ideas and problems that occupied him. Selye considered "Stress in heath and disease is medically, sociologically, and philosophically the most meaningful subject for humanity that I can think of".

A decade ago, Jurg Tschopp introduced the concept of the inflammasome. This exciting discovery of a macromolecular complex that senses 'danger' and initiates the inflammatory response contributed to a renaissance in the fields of innate immunity and cell death. Jurg led the biochemical characterization of the inflammasome complex and demonstrated that spontaneous hyperactivation of this interleukin (IL)-1β processing machinery is the molecular basis of a spectrum of hereditary periodic fever syndromes, caused by mutated forms of the inflammasome scaffolding receptor, NLRP3. The identification of the underlying mechanism in these disorders has led to their now successful therapy, with the use of the IL-1 receptor antagonist in the clinic. Jurg's pioneering work has subsequently defined a number of inflammasome agonists ranging from microbial molecules expressed during infection, to triggers of sterile inflammation, most notably gout-associated uric acid crystals, asbestos, silica and nanoparticles. More recently, Jurg introduced the critical new concept of the metabolic inflammasome, which senses metabolic stress and contributes to the onset of the metabolic syndrome associated with obesity and type 2 diabetes. Jurg was an outstanding and skillful biochemist, an elegant and rigorous researcher often far ahead of his peers. He was a truly amiable person, fair, generous and inspiring, and will be most remembered for his infectious enthusiasm. We write this review article on the inflammasome in his honor and dedicate it to his memory.

An overview of current concepts on neuroinflammation and on the dialogue between neurons and non-neuronal cells in three important infections of the central nervous systems (rabies, cerebral malaria, and human African trypanosomiasis or sleeping sickness) is here presented. Large numbers of cases affected by these diseases are currently reported. In the context of an issue dedicated to Camillo Golgi, historical notes on seminal discoveries on these diseases are also presented. Neuroinflammation is currently closely associated with pathogenetic mechanisms of chronic neurodegenerative diseases. Neuroinflammatory signaling in brain infections is instead relatively neglected in the neuroscience community, despite the fact that the above infections provide paradigmatic examples of alterations of the intercellular crosstalk between neurons and non-neuronal cells. In rabies, strategies of immune evasion of the host lead to silencing neuroinflammatory signaling. In the intravascular pathology which characterizes cerebral malaria, leukocytes and Plasmodium do not enter the brain parenchyma. In sleeping sickness, leukocytes and African trypanosomes invade the brain parenchyma at an advanced stage of infection. Both the latter pathologies leave open many questions on the targeting of neuronal functions and on the pathogenetic role of non-neuronal cells, and in particular astrocytes and microglia, in these diseases. All three infections are hallmarked by very severe clinical pictures and relative sparing of neuronal structure. Multidisciplinary approaches and a concerted action of the neuroscience community are needed to shed light on intercellular crosstalk in these dreadful brain diseases. Such effort could also lead to new knowledge on non-neuronal mechanisms which determine neuronal death or survival., (Copyright © 2010. Published by Elsevier B.V.)

The author was privileged to be an early contributor to the concept that cell adhesion molecules, the leukocyte (β2) integrins, play a pivotal role in the acute inflammatory process. For the author, this began with the development of a monoclonal antibody (anti-Mo1) that identified a differentiation antigen on the surface of human myeloid cells (including neutrophils, monocytes, and natural killer (NK) cells). Serendipitously, it was discovered that the Mo1 antigen was the heterodimeric glycoprotein (gp155,95) absent from the surface of neutrophils isolated from patients with adhesion defects in vitro and a syndrome characterized by chronic, life-threatening infections in vivo (a syndrome now termed leukocyte adhesion deficiency, type 1) (LAD-1). Collaborative efforts with other investigators (including members of the ACCA) revealed that patients with LAD-1 exhibited genetic mutations on chromosome 21 resulting in absent or diminished expression of a class of 4 surface adhesion molecules (now termed CD11a/CD18, CD11b/CD18, CD11c/CD18, and CD11d/CD18) known as the leukocyte or β2 family of integrins. Knowledge of the role of the β2 integrins in the acute inflammatory response led to the development of effective gene therapy strategies to treat LAD-1 in preclinical animal models and to the comprehensive testing of anti-integrin antibodies as anti-inflammatory agents to prevent organ damage as a complication of acute inflammation. This retrospective provides one illustration of the potential of bench-to-bedside research to generate new knowledge of clinical significance.

The causes of laminitis are many-often interrelated, sometimes direct opposites. The history of laminitis has been a search for the cause or causes of laminitis and for effective treatment. Going in and out of fashion, many treatments have lasted for centuries, some for millennia, but very few have been proven., (Copyright 2010 Elsevier Inc. All rights reserved.)

Inflammation is an essential immune response that enables survival during infection or injury and maintains tissue homeostasis under a variety of noxious conditions. Inflammation comes at the cost of a transient decline in tissue function, which can in turn contribute to the pathogenesis of diseases of altered homeostasis., (2010 Elsevier Inc. All rights reserved.)

Although there has been a great amount of progress in the 25 years since the first reporting of the cDNA for IL-1alpha and IL-1beta, the history of IL-1 goes back to the early 1940s. In fact, the entire field of inflammatory cytokines, TLR and the innate immune response can be found in the story of IL-1. This Viewpoint follows the steps from the identification of the fever-inducing activities of "soluble factors" produced by endotoxin-stimulated leukocytes through to the discovery of cryopyrin and the caspase-1 inflammasome and on to the clinical benefits of anti-IL-1beta-based therapeutics. It also discusses some of the current controversies regarding the activation of the inflammasome. The future of novel anti-inflammatory agents to combat chronic inflammation is based, in part, on the diseases that are uniquely responsive to anti-IL-1beta, which is surely a reason to celebrate the 25th anniversary of the cloning of IL-1alpha and IL-1beta.

In this review, the author discusses the research that led to the identification and characterization of interleukin 6 (IL-6), including his own experience isolating IL-6, and the roles this cytokine has on autoimmune and inflammatory diseases. The cDNAs encoding B-cell stimulatory factor 2 (BSF-2), interferon (IFN)-beta2 and a 26-kDa protein were independently cloned in 1986, which in turn led to the identification of each. To resolve the confusing nomenclature, these identical molecules were named IL-6. Characterization of IL-6 revealed a multifunctional cytokine that is involved in not only immune responses but also hematopoiesis, inflammation, and bone metabolism. Moreover, IL-6 makes significant contributions to such autoimmune and inflammatory diseases as rheumatoid arthritis (RA).IL-6 activates both the STAT3 and SHP2/Gab/MAPK signaling pathways via the gp130 signal transducer. F759 mice, which contain a single amino-acid substitution in gp130 (Y759F) and show enhanced STAT3 activation, spontaneously develop a RA-like arthritis as they age. F759 arthritis is dependent on CD4(+) T cells, IL-6, and IL-17A, and is enhanced by the pX gene product from human T cell leukemia virus 1 (HTLV-1). Arthritis development in these mice requires that the F759 mutation is present in nonhematopoietic cells, but not in immune cells, highlighting the important role of the interaction between nonimmune tissues and the immune system in this disease. Furthermore, this interaction is mediated by the IL-6 amplifier through STAT3 and NF-kappaB. Ultimately, this model may represent a general etiologic process underlying other autoimmune and inflammatory diseases. More importantly, the understanding of IL-6 has paved the way for new therapeutic approaches for RA and other autoimmune and inflammatory diseases.

In Rudolf Virchow's concept of inflammation, the basic alterations were derived from connective tissue cells, which underwent a marked metamorphosis. This cell-based and static conception was fundamentally broadened and, in part, refuted in the ensuing decade by 2 of his scholars. Friedrich Daniel von Recklinghausen characterized the pus cells in acute inflammation and made the seminal observation of their contractility and mobility. He was the first who described the wandering leukocytes which were demonstrated in particular in experimental keratitis. He also showed that pus cells could migrate from the places of their origin in the interstitium to other tissues and epithelial cells. Von Recklinghausen in addition contributed to the concept of phagocytosis. The work of Julius Friedrich Cohnheim was focused on the mechanisms involved in the extravasation of leukocytes from the blood vessels in the inflamed mesentery of the frog and carefully described the time-dependent alterations: dilatation of the arteries and veins, adhesion of colorless cells to the endothelial cells, and the subsequent transmigration from the capillaries and venules into the interstitial space. In the last few decades, experimental and clinical studies using modern techniques have fully confirmed and extended these basic observations made by von Recklinghausen and Cohnheim more than 100 years ago.

Ideas of I.I Mechnikov stated in biologic theory of inflammation and, specifically, about leading role of phagocytic cells are getting more and more prevalent. Special attention is paid to study of Toll-like receptors (TLRs) and cytokines roles in initiation of inflammatory reaction. TLRs are present not only on immune system's cells but virtually on all cells of an organism. On the basis of these data we proposed the hypothesis designated as "one receptor-many cells" and "one receptor-one cell". In the former case the leading role in recognition of antigen belongs to TLRs then followed by other organism's cells, which is characteristic for innate immunity. In the latter case recognition is realized through T- and B-cell receptor presented only on lymphocytes, which is characteristic for adaptive immunity. New class of lipid mediators (rezlovins, protectins etc.) involved in stage of inflammation resolve is revealed. This means that drugs with antiinflammatory activity can act according to principle "go-stop". Complex of natural cytokines and cationic antimicrobial peptides (Superlymph) possesses such effect.

Throughout the 20th century, an understanding of the role of causative bacteria and the susceptible host in the initiation and progression of periodontal disease(s) has emerged from the research efforts of scientists and clinicians worldwide. Over time, specific bacterial types, such as Porphyromonas gingivalis, were discovered and shown to be important in the cause of periodontal disease. At the same time, inflammatory mediators, such as prostaglandins and interleukins, and enzymes, such as matrix metalloproteinases, were discovered and found to be important participants in the destruction of periodontal tissues. Acquired and inherited environmental risk factors began to emerge that could explain, in part, the susceptibility of individuals to periodontal disease. The discovery of antibiotics, beginning with sulfanilamide, penicillin, and streptomycin, led to additional strategies for managing periodontal disease. With the discovery of the mechanism of action of aspirin, scientists began to develop new strategies for treating diseases that focused on controlling inflammation. Thus, host-modulating therapies emerged for the management of periodontal disease through the control of inflammation. At the end of the 20th century, an old concept in medicine and dentistry reappeared: that the infection and inflammation of periodontal disease in the mouth could reach distant sites via the bloodstream. Apparently oral disease could, in fact, contribute to systemic diseases, such as atherosclerosis, diabetes, and adverse outcomes in pregnancy. This concept of the oral health-general health connection is now supported by sound and rational evidence-based observations. Clearly, the 21st century has arrived with a new understanding of the nature of periodontal diseases based on a notable era of discovery. There is a promising future for preventing and treating this common and troubling condition that affects not just the mouth but also the whole body.

After a decade of the "modern era" of zebrafish hematology research, what have been their major contributions to hematology and what challenges does the model face? This review argues that, in hematology, zebrafish have demonstrated their suitability, are proving their utility, have supplied timely and novel discoveries, and are poised for further significant contributions. It presents an overview of the anatomy, physiology, and genetics of zebrafish hematopoiesis underpinning their use in hematology research. Whereas reverse genetic techniques enable functional studies of particular genes of interest, forward genetics remains zebrafish's particular strength. Mutants with diverse and interesting hematopoietic defects are emerging from multiple genetic screens. Some mutants model hereditary blood diseases, occasionally leading to disease genes first; others provide insights into developmental hematology. Models of malignant hematologic disorders provide tools for drug-target and pharmaceutics discovery. Numerous transgenic zebrafish with fluorescently marked blood cells enable live-cell imaging of inflammatory responses and host-pathogen interactions previously inaccessible to direct observation in vivo, revealing unexpected aspects of leukocyte behavior. Zebrafish disease models almost uniquely provide a basis for efficient whole animal chemical library screens for new therapeutics. Despite some limitations and challenges, their successes and discovery potential mean that zebrafish are here to stay in hematology research.

The only Confederate president, Jefferson Davis, led a long and eventful life. He was a Mississippi planter, a husband, a father, West Point graduate, war hero, congressman, senator, secretary of war, and finally President of the Confederate States of America. In many ways he was a study of contrast with his northern counterpart Abraham Lincoln. Davis was personally courageous and a rich, educated, southern aristocrat who did not deeply understand the political process or have the refined personal skills necessary to work well with others. Prior to his Presidency he served with distinction in two wars, but as a result of his confederate activity and pro-slavery philosophy he is one of the least discussed famous Americans. Davis's health was a constant problem and he suffered an almost fatal attack of 'malaria' in 1836. In the winter of 1857-1858, he again was seriously ill and by the end of February 1858, a chronic, relapsing, ocular inflammatory condition began. Using historical evidence from multiple sources, this paper will propose a diagnosis of the Confederate President's ocular condition and consider how this could have influenced his military and political decisions.

The history of atherosclerosis represents a very interesting and intriguing charter of the history of medicine. Atherosclerosis was present even in the old age, as demonstrated by paleopathological studies. Starting from these observations, recent evidences highlighted the crucial role of inflammation in the genesis of atherosclerosis.

It is now clear that inflammation plays a key role in atherogenesis. As a matter of fact, signs of inflammation of atherosclerotic plaques have been observed for centuries and also constituted the basis for a fierce controversy in the 19th century between the prominent Austrian pathologist Carl von Rokitansky and his German counterpart, Rudolf Virchow. While the former attributed a secondary role to these inflammatory arterial changes, Virchow considered them to be of primary importance. We had the unique opportunity to address this controversy by investigating atherosclerotic specimens from autopsies performed by Carl von Rokitansky up to 178 years ago. Twelve atherosclerotic arteries originally collected between the years 1827 to 1885 were selected from the Collection Rokitansky of the Federal Museum of Pathological Anatomy, Vienna Medical University. Using modern sophisticated immunohistochemical and immunofluorescence techniques, it was shown that various cellular intralesional components, as well as extracellular matrix proteins, were preserved in the historic atherosclerotic specimens. Most importantly, CD3 positive cells were abundant in early lesions, thus, rather supporting Virchows's view, that inflammation is an initiating factor in atherogenesis. Furthermore, we hope to have opened a new and intriguing possibility to study various pathological conditions using valuable historical specimens.

In 1947, Paul Beeson showed that rabbits repeatedly injected with certain bacteria eventually become resistant to the bacteria's fever-provoking effects-a phenomenon known as endotoxin tolerance.

People have used the words inflammation and fever for millennia, but the meaning of inflammation has gradually changed whereas that of fever has remained reasonably constant. Whereas inflammation originally referred to the combination of heat, redness, swelling and pain in a local area, it has gradually evolved to focus upon cellular and humoral processes that occur in tissues when external or internal agents cause damage to them. The classical manifestations are no longer obligatory. Diseases that affect internal organs such as the kidneys are nowadays commonly described as inflammatory despite entirely lacking those classical manifestations, but possessing evidence of cellular proliferation and/or involvement of factors such as cytokines. These conceptual changes have resulted from the application of progressively improved investigational techniques such as microscopy, thermometry, experimental pathology, and tissue culture. The consequence of them has been largely to extinguish the fire that previously epitomised inflammation.

At the beginning of the 19th century, medicine was based largely on speculative and philosophical concepts. The greatest merit of Rudolf Virchow was without doubt a way of thinking based on natural science. In place of the empirical chaos represented by the doctrines of humors and crasis, he created the new paradigm of cellular pathology. In the field of inflammation, he critically analyzed the meaning of the four key symptoms of inflammation (redness, swelling, heat and pain) and postulated that inflammation cannot be represented as a single process but rather constitutes various inflammatory processes. In addition he introduced the functio laesa , denoting the restricted function of inflamed tissues. In the pathogenesis of inflammation, Virchow highlighted the importance of the inflammatory stimulus. The irritatio is the starting point and the conditio sine qua non . Through his pathohistological investigations in experimental animals and in humans, inflammation was widely accepted as the central cause of atherosclerosis, until the end of the 19th century, and has been confirmed in recent decades. It was Virchow who first coined the term endarteriitis deformans . Likewise, he was also the first to hypothesize a link between microinflammation and subsequent cancer development. This hypothesis has recently been corroborated by numerous studies and may have therapeutic consequences. Virchow contributed to nearly all aspects of human pathology and championed the cause of social medicine.