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Keywords:

  • William Ostler;
  • internal medicine;
  • haematology;
  • microscopy;
  • platelets;
  • pernicious anaemia;
  • polycythemia vera

William Osler (1849–1919) is generally regarded as one of the greatest and most admired physicians in the history of medicine. An outstanding clinician, he possessed extraordinary charm which inspired many pupils. Osler stressed bedside teaching, hard work, medical history and lifelong learning. As Professor of Medicine at four institutions in three countries, he exerted a profound influence on medical education. A prolific writer, his textbook became the most popular and widely read treatise on medicine in the world. His humanistic philosophy was reflected in all aspects of his life. Osler blended the art and science of medicine perhaps better than anyone else and remains a valuable role model for students and physicians.

Osler's early experience with the microscope as a schoolboy led to important contributions to haematology. He was among the first to recognize platelets as the third formed element of the blood; he documented their importance in thrombosis. His early studies on pernicious anaemia have been largely neglected, but his thorough descriptions of polycythaemia vera and hereditary haemorrhagic telangiectasia popularized both entities. Most significant of all, Osler brought the microscope to the clinic and emphasized the value of examination of the blood in clinical diagnosis.

Osler's role in the development of internal medicine

  1. Top of page
  2. Osler's role in the development of internal medicine
  3. Osler's Contribution to Haematology ()
  4. Osler and the microscope
  5. Platelets
  6. Pernicious anaemia (PA)
  7. Polycythaemia vera (Osler–Vaquez disease)
  8. Malaria
  9. Splenic anaemia
  10. Hereditary haemorrhagic telangiectasia (HHT) (Osler–Weber–Rendu disease)
  11. Other conditions
  12. Acknowledgments
  13. Note added in Proof
  14. References

Osler occupies a unique position in the history of medicine. He is generally acknowledged as one of the most outstanding clinicians and teachers of all time (Dana, 1919; Cushing, 1925; Abbott, 1926; Reid, 1931; Bailey, 1993; Stone, 1995). Many of Osler's writings (Osler, 1904a, 1907a, 1908a, 1913, 1921; Camac, 1906; Verney, 1960; McGovern & Roland, 1969, 1985; Roland, 1982; Nation, 1987; Hinohara & Niki, 2001; Silverman et al, 2003) have inspired and been cherished by medical students and physicians throughout the world. His close personal relationship with students and colleagues has been amply documented (Pratt, 1949; Nation & McGovern, 1980; Howard, 1983; Golden, 1992a). Commemorative issues of several journals have appeared in his honour (Osler Memorial Issue, 1949; William Osler Anniversary Issue, 1949; Roland, 1969), a number of bibliographies of his writings have been published (Blogg, 1921; Abbott, 1939; Nation et al, 1976; Golden & Roland, 1988), and his likeness has been preserved on many portraits, busts and medals (Sakula, 1991). A new biography appeared in the sesquicentennial year of his birth (Bliss, 1999), the first full-length account of Osler's life since Cushing's Pulitzer prize-winning treatise published in 1925. The Osler Society of McGill University was founded in 1921, the Osler Club of London in 1928, the American Osler Society in 1970 (Barondess et al, 1985; Barondess & Roland, 1994, 2002) and the Japanese Osler Society in 1983. In May 2003, a joint meeting of the American, London and Japanese Osler organizations was held in Edinburgh, UK. Thus, Osler remains one of the most revered physicians of modern times (Golden, 1999a).

William Osler was born in Bond Head near Toronto in 1849, the eighth of nine children (Table I) (Talbott, 1969; Roland, 1984; Bliss, 1999). His mother lived past the age of 100 years; his father was an Anglican clergyman. As a bright, high-spirited youngster, Willie got into his fair share of trouble – he was expelled from grammar school for abusive language and once filled a schoolroom with geese after moving the desks to an attic. At private school, he met Reverend W. A. Johnson, who introduced him to biology and the microscope. This interest in microscopy was to become one of the dominant themes of his career. He enrolled in Trinity College at Toronto and originally planned to follow his father into the clergy. After being influenced by a physician, Dr James Bovell, Osler switched to medicine (Silverman, 1993). He entered Toronto Medical School and transferred to McGill for his final 2 years. There, he came into contact with the well-known clinician and teacher, R. Palmer Howard. Johnson, Bovell and Howard were the three teachers to whom Osler later dedicated his textbook. He received his MD degree in 1872 from McGill and then travelled to England and continental Europe. Osler's experience abroad made him a proponent of postgraduate travel. His trip was the first of what later became known as ‘brain-dusting excursions’. He spent 17 months in London at University College Hospital in the physiology laboratory of John Burdon Sanderson (whom he would succeed as Regius Professor of Medicine at Oxford 33 years later), during which time he became one of the first to recognize the platelet as the third formed element in the blood and documented the importance of platelets in thrombus formation (Osler, 1886a). He also visited Germany and came into brief contact with the great Rudolph Virchow. On returning to Canada, he began working as a general practitioner. A few months later, he was invited to join the medical faculty at McGill.

Table I.  William Osler chronology.
1849 – Born 12 July at Bond Head, near Toronto, Ontario, Canada
1869 – First publication: Christmas & the Microscope
1872 – MD, McGill
1872–74 – Postgraduate travel to England (Burdon Sanderson's laboratory) and Europe
1874–84 – McGill faculty (rose to Professor)
1884–89 – University of Pennsylvania faculty (Professor of Clinical Medicine)
1889–1905 – Johns Hopkins faculty (Physician-in-Chief, Professor)
1892 –Principles and Practice of Medicine (1st edition)   Married Grace Revere Gross
1895 – Son (Edward) Revere born
1905–19 – Oxford faculty (Regius Professor of Medicine)
1909 –Principles and Practice of Medicine (7th edition)
1911 – Baronetcy
1917 – Revere killed in Flanders in World War I
1919 – Died December 29

No bubble is so iridescent or floats longer than that blown by the successful teacher ’ (Osler, 1911)

During his 10 years on the McGill faculty (1874–1884), Osler rose to the rank of professor. He was quickly recognized as an outstanding clinician and stimulating teacher, always emphasizing the role of bedside teaching and observation. He also served as a pathologist to a smallpox hospital, maintained a small private practice and published many papers dealing with various clinical, pathological and veterinary subjects. During this decade, Osler organized medical clubs and achieved unusual popularity engendered by his exemplary conduct and generosity.

Medicine is learned by the bedside and not in the classroom ’ (Thayer, 1931)

Osler performed nearly 1000 autopsies; this experience, combined with his knowledge of microscopy, made him well grounded in morbid anatomy and contributed much to his understanding of the natural history of disease and the importance of clinicopathological correlation (Robb-Smith, 1981; Rodin, 1981).

Now the way of life that I preach is a habit to be acquired gradually by long and steady repetition. It is the practice of living for the day only, and for the day's work. Life in day-tight compartments' (Osler, 1913)

Osler left Montreal in 1884 to become Professor of Clinical Medicine at the University of Pennsylvania. His reputation and productivity continued to grow in Philadelphia. He gave his famous address, Aequanimitas, to the University of Pennsylvania graduating class in 1889. That year, he became Chief of Medicine at the new Johns Hopkins Hospital and Medical School, where he remained until 1905 (Fig 1).

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Figure 1. William Osler in 1905. From a photograph by William Notman, Montreal. Reproduced (with permission from the Secretary-Treasurer of the US and Canadian Academy of Pathology) from Abbott (1926).

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‘In the physician or surgeon no quality takes rank with imperturbability ’ (Osler, 1904b)

Osler was instrumental in establishing Johns Hopkins as the outstanding institution of medical education in the United States (Starr, 1982; Ludmerer, 1985, 1999; Harvey et al, 1989, 1990). He helped to found the new school and was one of the ‘Big Four’ of Hopkins along with Welch, Halsted and Kelly (Southgate, 1989). He introduced the clinical clerkship and created the template of graded responsibility among students and house officers that survives to the present day (Ludmerer, 1985, 1999; Beeson & Maulitz, 1988). He continued to emphasize the importance of direct interaction with patients and careful clinical observation. He stressed the value of medical history and wrote many inspirational essays. For him, the master word in medicine was indeed ‘work’ (Osler, 1904c). During his tenure at Hopkins, Osler acquired an international reputation and became one of the most respected clinicians in the world (Fig 2).

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Figure 2. Osler at the bedside. From Cushing (1925) (reproduced with the permission of Oxford University Press).

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Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease ’ (Osler, 1904d)

Start out with the conviction that absolute truth is hard to reach in matters relating to our fellow creatures, healthy or diseased, that slips in observation are inevitable even with the best-trained faculties, that errors in judgement must occur in the practice of an art which consists largely in balancing probabilities ’ (Osler, 1904e)

In 1892, Osler's textbook, The Principles and Practice of Medicine, appeared and became the leading treatise on general medicine in the world for the next 40 years (Osler, 1892a; Harvey & McKusick, 1967; Beeson, 1986; Fye, 1987; Golden, 1992b). He personally revised the book through seven editions.

Two quotations appear in the front of the book:

Experience is fallacious and judgement difficult ’ – Hippocrates: Aphorisms I

And I said of medicine, that this is an art which considers the constitution of the patient, and has principles of action and reasons in each case ’ – Plato: Georgias

The misspelling of Gorgias identifies the first printing of the textbook; the error was corrected in the second printing and subsequent editions. The enormous influence and popularity of the textbook were evident from its sales and its translation into French, German, Russian, Spanish, Portuguese and Chinese editions. It was also indirectly responsible for the formation of the Rockefeller Institute for Medical Research (Beeson, 1986; Golden, 1992b; Edelson, 1994). The textbook emphasized aetiology, pathogenesis and diagnosis, and reflected Osler's great knowledge of clinical medicine and pathology. Lucidly written with many historical references, it was said that Osler ‘succeeded in making a scientific treatise literature’. However, he became known as a therapeutic nihilist (Thomas, 1983; Beeson, 1986; Beeson & Maulitz, 1988). On balance, one should recall that not many effective medical treatments existed in the latter part of the nineteenth century.

Do not rashly use every new product of which the peripatetic siren sings. Consider what surprising reactions may occur in the laboratory from the mixing of unknown substances. Be as considerate of your patient and yourself as you are of the test-tube ’ (Thayer, 1931)

Grace Revere Osler was the great granddaughter of Paul Revere and the widow of Osler's friend, Doctor Samuel W. Gross, the Philadelphia surgeon who helped recruit Osler to the University of Pennsylvania (Muirhead, 1931; Harrell, 1982, 1985; Wagner, 1985). Grace and William were married in May 1892, shortly after publication of the textbook. They had two children, Paul Revere who survived only briefly, and Edward Revere, born in 1895.

Osler left Baltimore in 1905 to assume his new position as Regius Professor of Medicine at Oxford (replacing his mentor, Burdon Sanderson) where he lived for the remainder of his life (Malloch, 1921; Cushing, 1925; Fye, 1989; Bliss, 1999). He thought that Oxford would offer a more relaxing atmosphere so that he could retire gradually, but he was soon as busy as he had been in Baltimore (Roland, 1984). The Osler home at 13 Norham Gardens became known as the ‘Open Arms’ to students, colleagues and friends. Osler continued to found medical organizations and journals including the Quarterly Journal of Medicine. He served as curator of the Bodleian Library. In the pattern of Virchow, Osler vigorously supported public health and sanitary measures. He continued clinical teaching, collected books, published papers and practised medicine. A baronetcy was conferred on him in 1911. The tragedy of his life occurred in 1917 when his son, Revere, was killed in Flanders in World War I. In 1919, Osler developed pneumonia and died on 29 December (Hinohara, 1993). His last formal presentation was the inaugural address as president of the British Classical Association 6 months before his death (Osler, 1920).

A prolific writer, Osler had over 1600 items in his bibliography (Golden & Roland, 1988; Golden, 1999a). His first publication described the appearance of pond water under the microscope (Osler, 1869). His important original observations on blood platelets were made in 1873 when he was 24 years old. Approximately 8% of his publications dealt with haematology, oncology or the microscope. Nearly one-third of his scientific papers were devoted to topics on cardiovascular disease (Pruitt, 1982; Fye, 1985). Osler's clinical investigative and research background provided him with an insightful perspective.

The greater the ignorance the greater the dogmatism ’ (Osler, 1904f)

The philosophies of one age have become the absurdities of the next, and the foolishness of yesterday has become the wisdom of tomorrow ’ (Osler, 1904f)

Thousands of men with keen eyes had watched the heart beat, had seen arteries spurt red blood, had seen the black blood flow from the veins, and they had thought and thought and thought of how the heart beat and how the blood flowed, but all in vain until, in a few simple experiments, the problem of its circulation was demonstrated ’ (Osler, 1911)

Osler continually emphasized the importance of bedside teaching and clinical laboratory microscopy, the ongoing necessity to read throughout one's career and the recognition of contributions by previous physicians. He was always in direct contact with students (his chosen epitaph was ‘I taught medical students on the wards’), and often hosted informal meetings with them on Saturday evenings at his home. In Baltimore and Oxford, many were given keys to his front door so that they could take advantage of his outstanding library; these students became known as the ‘Latch Keyers’.

Just as the embryo passes through life of lower grade, before resulting in the thinking man – the ontogeny reproducing the phylogeny – so the career of the medical student follows the evolution of the marvelous knowledge that has made our profession the most helpful of all to humanity ’ (Osler, 1911)

To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all ’ (Osler, 1904g)

Osler cultivated a lifelong interest in the history of medicine and the humanities (Osler, 1921; Fulton, 1949; Bensley & Bates, 1976; Wallis, 1986). His humanistic philosophy and conduct were reflected in all aspects of his life. He emphasized the importance of the classics and of regular reading at bedtime (Osler, 1904a; Rakel, 1988; Bryan, 2002). His personal library contained over 7000 books, which he bequeathed to McGill University (Osler, 1929; The Osler Library, 1979). Always a prankster, he humorously wrote under a pseudonym, Egerton Yorrick Davis, sometimes criticizing his own (i.e. Osler's) writings (Bean, 1966; Nation, 1969; Golden & Roland, 1988; Golden, 1999b).

Osler constantly reminded students of the high ideals of the medical profession and the human side of patient care:

Care more particularly for the individual patient than for the special features of the disease ’ (Bean & Bean, 1961a)

To have striven, to have made an effort, to have been true to certain ideals – this alone is worth the struggle ’ (Osler, 1908b)

However, Osler was not just a kindly old clinician who liked to teach and write. He recognized the need to be critical of colleagues (Roland, 1974). He applied the latest advances in medicine to the care of his patients – whether it was the use of newly described stains in the interpretation of blood smears or urging the Board of The Johns Hopkins Hospital to acquire an X-ray machine within a few months of Röntgen's first publication announcing its discovery (Conn, 1985). Osler realized that advances in scientific medicine greatly enhanced the clinician's effectiveness in patient care, and he welcomed them (Osler, 1915). It seems likely that Osler would be squarely in the forefront of advances in medical science if he were alive today.

It is astonishing with how little reading a doctor can practice medicine, but it is not astonishing how badly he may do it ’ (Osler, 1904g)

To wrest from nature the secrets which have perplexed philosophers in all ages, to track to their sources the causes of disease, to correlate the vast stores of knowledge, that they may be quickly available for the prevention and cure of disease – these are our ambitions ’ (Osler, 1904f)

In this era of ongoing debate on health care reform and delivery, it is essential to keep in mind how patients are cared for, how medical students are taught and how medical science advances through carefully conducted research. In this context, Osler's wisdom is everlasting. Its universality and timeless relevance are guideposts. Osler's emphasis on the importance of hard work, close observation, ongoing education and a practical approach to the day's activities build the foundation for effective application of scientific knowledge in diagnosis and treatment. His wit, humour, warmth, compassion and humane concern for patients and colleagues are traits we strive to emulate. His example and precepts provide the core qualities that define what it means to be a physician. Osler said, ‘the old art cannot possibly be replaced by, but must be absorbed in, the new science’ (Osler, 1907a). He put the art and science of medicine together as well as anyone ever has. Osler remains a role model for us all.

Osler's Contribution to Haematology (Table II)

  1. Top of page
  2. Osler's role in the development of internal medicine
  3. Osler's Contribution to Haematology ()
  4. Osler and the microscope
  5. Platelets
  6. Pernicious anaemia (PA)
  7. Polycythaemia vera (Osler–Vaquez disease)
  8. Malaria
  9. Splenic anaemia
  10. Hereditary haemorrhagic telangiectasia (HHT) (Osler–Weber–Rendu disease)
  11. Other conditions
  12. Acknowledgments
  13. Note added in Proof
  14. References
Table II.  Osler's contribution to haematology.
Original observations on platelets and their role in thrombosis
Pernicious anaemia – clinical and haematological findings; description of gastric atrophy
Confirmation of Laveran's discovery of malaria diagnosis
Polycythaemia vera (Osler–Vaquez disease)
Hereditary haemorrhagic telangiectasia (Osler–Weber–Rendu disease)
Description and potential mechanisms of splenic anaemia
Early description of adult urticaria pigmentosa
Many papers/chapters on anaemias, purpuras, leukaemia and Hodgkin's disease
Taught clinical microscopy and emphasized the importance of blood examination in diagnosis

Osler and the microscope

  1. Top of page
  2. Osler's role in the development of internal medicine
  3. Osler's Contribution to Haematology ()
  4. Osler and the microscope
  5. Platelets
  6. Pernicious anaemia (PA)
  7. Polycythaemia vera (Osler–Vaquez disease)
  8. Malaria
  9. Splenic anaemia
  10. Hereditary haemorrhagic telangiectasia (HHT) (Osler–Weber–Rendu disease)
  11. Other conditions
  12. Acknowledgments
  13. Note added in Proof
  14. References

Osler was introduced to the microscope, as a schoolboy, by his mentor Reverend Johnson, and his interest developed further under the influence of Dr Bovell. Osler's first publication (at age 19) was entitled Christmas and the microscope (Osler, 1869). In the paper he stated, ‘The earth has put on her winter robes, and under them she hides most of those objects which in summer please and delight us so much. A cheerless prospect for microscopists, one would think… Upon putting a slide under the microscope before I had it properly focused, I saw the dim outline of some little creature kicking and struggling as though it were caught in a net’. Through Reverend Johnson and Dr Bovell, Osler acquired a copy of Lionel Beale's How to Work with the Microscope (Beale, 1865; Robb-Smith, 1981) in 1868. Shortly after receiving Beale's book, young Willie decided to become a doctor rather than a member of the clergy. After 2 years at the Toronto medical school, he moved to McGill. His first clinical paper written while still a medical student described the gross and microscopic findings of a patient with breast cancer (Osler, 1871). Osler's graduation thesis in 1872 dealt with histopathology. By the time he received the MD degree, Osler was an accomplished microscopist. He used this skill to great advantage in his postgraduate study and became a staunch advocate of the value of microscopy in medicine. Osler taught microscopy to students at McGill, brought the first microscope to the University of Pennsylvania Hospital and established the Clinical Microscopy Laboratory at Johns Hopkins. A special meeting of the Johns Hopkins Historical Club was held in 1925, at which time a memorial plaque was presented to the hospital by 50 of Osler's colleagues and friends (Special meeting of the Johns Hopkins Historical Club, 1927) (Fig 3). Dr R. Tait McKenzie, the artist who executed the plaque, said it was ‘intended to represent Dr Osler at a clinical lecture. The hand is stretched out to his microscope that was always his faithful companion’.

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Figure 3. The memorial plaque created byDr R. Tait McKenzie and donated to the Johns Hopkins Hospital by Osler's friends and colleagues, 19 January 1925 (reproduced with permission from the Secretary-Treasurer of the US and Canadian Academy of Pathology).

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Platelets

  1. Top of page
  2. Osler's role in the development of internal medicine
  3. Osler's Contribution to Haematology ()
  4. Osler and the microscope
  5. Platelets
  6. Pernicious anaemia (PA)
  7. Polycythaemia vera (Osler–Vaquez disease)
  8. Malaria
  9. Splenic anaemia
  10. Hereditary haemorrhagic telangiectasia (HHT) (Osler–Weber–Rendu disease)
  11. Other conditions
  12. Acknowledgments
  13. Note added in Proof
  14. References

The discovery of platelets involved several investigators during the period between 1840 and 1890 (Tocantins, 1949; Robb-Smith, 1967, 1981, 1992; Spaet, 1980). The first suggestion of blood elements other than red cells and leucocytes had been raised by Hewson and Andral. However, it is unlikely that platelets could be seen before 1830, when J. J. Lister devised a lens combination for microscopes that reduced aberration, thus improving resolution. George Gulliver has been credited with the first illustration of platelets about 1841, and William Addison (also an Englishman apparently unrelated to Thomas) published a drawing of a platelet–fibrin clot in 1842.

The same year, Alfred Donné noted that there existed in the blood red and white globules and little globules, implying that he had recognized a distinct morphological element in the blood. Lionel Beale, the father of English clinical pathology and author who taught young Osler much about microscopy, published an article in 1864 with a drawing of human blood clearly showing platelets, although his interpretation of their origin was erroneous (Beale, 1864). When Osler arrived in England to study in Burdon Sanderson's physiology laboratory (Fig 4), he initially studied the effects of various drugs on leucocytes under the supervision of Edward Schaefer. In looking at his own blood, however, Osler's attention became drawn to other elements, which he thought were similar to the granular masses described by Max Schultze (Conley, 1985). In 1873–74, Osler examined the blood in subcutaneous and mesenteric vessels of freshly killed rats and pointed out that the granular masses of Schultze resulted from agglutination of small bodies which occurred as single units in the circulation (Osler & Schafer, 1873; Osler, 1874). These ‘pale round discs’ were ‘1/8 to 1/2 the size of a red corpuscle’. His illustration clearly showed that these granular masses occurred as single elements in the circulating blood, which came together when the blood was shed. Osler was not sure what they were, perhaps bacteria, and unfortunately referred to ‘organisms’ in the title of his paper. On returning to Montreal, Osler continued his studies of platelets. In 1881, he spoke on ulcerative endocarditis, a subject in which he maintained interest for his entire life (Osler, 1881a). He observed the aggregation of granular bodies in the vegetations on heart valves but also saw the bacteria on the vegetations, so again there was confusion between platelets and bacteria. In another report, Osler showed that a thrombus on an atheromatous plaque consisted predominantly of platelets (Osler, 1882a).

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Figure 4. Osler during his postgraduate stay in London (Abbott, 1926; opposite p. 175) (reproduced with permission from the Secretary-Treasurer of the US and Canadian Academy of Pathology).

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Julius Bizzozero (1881) confirmed that platelets were distinct elements that circulated in the blood of living animals. Bizzozero ignored Osler's work on platelets, but a short article set the record straight (Osler, 1883). In 1886, Osler was invited to give the Cartwright Lectures at the College of Physicians and Surgeons in New York. He selected the topic, ‘On certain problems in the physiology of blood corpuscles’. The three lectures consisted of a review of both his own and others' work on blood platelets, coagulation and thrombosis (Osler, 1886a). Osler discussed platelet aggregation that occurred in shed blood, which he had described in his 1873 paper when he equated the aggregates with Schultze's granular masses. He stated that the third corpuscle or blood ‘plaque’ was a colourless protoplasmic disc, constant in mammalian blood, measuring from 1·5 to 3·5 micromillimetres (Fig 5). ‘The number per cubic millimeter in the blood of a healthy adult is about 250,000, but their number varies greatly at different periods of life and with varying conditions of health and disease’. In Lecture Two, he stated, ‘this it is which makes the blood such a puzzle, for the corpuscles, so far as observation goes, neither die nor are born in the circulating fluid, but appear to enter it as perfect elements and are removed from it before they are so changed as to be no longer recognizable’. In the third Cartwright Lecture, Osler said, ‘what I contend is, that the white thrombi are composed chiefly of plaques, and that the colourless corpuscles play an altogether insignificant part in their formation…’. Osler's observations emphasized the role of platelets in thrombosis and confirmed the views of George Hayem and Bizzozero.

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Figure 5. Osler's drawings of platelets. Cartwright Lecture I 1886.

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The Cartwright Lectures were the last of Osler's experimental observations on platelets. In 1905, he took part in a symposium held at Johns Hopkins (Osler, 1905). When another speaker announced that platelets examined on the top of Pike's Peak contained haemoglobin, Osler remarked that he had seen many platelets, but never one that blushed!

William Osler made some of the earliest key observations that identified platelets as a normal component of blood and linked their function with thrombus formation. Although Osler's studies on platelets were probably his most significant original scientific contribution, they have not generally received much attention – barely one page (out of 1371) in the Cushing biography (Cushing, 1925). In the large memorial volume published in 1926, they are hardly mentioned (Abbott, 1926).

Pernicious anaemia (PA)

  1. Top of page
  2. Osler's role in the development of internal medicine
  3. Osler's Contribution to Haematology ()
  4. Osler and the microscope
  5. Platelets
  6. Pernicious anaemia (PA)
  7. Polycythaemia vera (Osler–Vaquez disease)
  8. Malaria
  9. Splenic anaemia
  10. Hereditary haemorrhagic telangiectasia (HHT) (Osler–Weber–Rendu disease)
  11. Other conditions
  12. Acknowledgments
  13. Note added in Proof
  14. References

It is difficult to know which of the patients described by James Combe, Thomas Addison, Antoine Biermer and others during the 50 years after 1824 actually had pernicious anaemia (Chanarin, 2000).

Addison had been studying chronic fatal idiopathic anaemia for some years before he wrote in 1855, ‘it makes its approach in so slow and insidious a manner, that the patient can hardly fix a date to his earliest feeling of that languor which is soon to become so extreme…’.

Despite the lack of clear-cut clinical and laboratory findings, Addisonian anaemia was attributed to atrophy of the stomach by Austin Flint in 1860, a finding confirmed microscopically by Samuel Fenwick (1870).

In 1877, William Gardner and Osler reported a case of ‘progressive pernicious anaemia’. The term had been used 5 years before by Biermer, who described it as a new disease. This aroused much interest and also defence of Addison's priority by Samuel Wilks and others. Gardner and Osler's case was probably the first in which the clinical, haematological and pathological features were described in sufficient detail to leave little doubt that it was Addisonian PA as currently defined. The patient was a 52-year-old Englishman who complained of weakness and dyspnoea on exertion, numbness of the fingers and hands (difficulty buttoning his clothes) and a throbbing sensation in his temples. He died of progressive symptoms 2 months later. In the peripheral blood, Osler described macroovalocytes and marked variation in size and shape of the red cells. At autopsy, generalized pallor, a peculiar lemon tint to the skin and a thin gastric membrane were observed. The bone marrow disclosed intense hyperplasia and was filled with large nucleated red cells having homogeneous stroma and a finely granulated nucleus. This was the first clear description of the megaloblast (Robb-Smith, 1981; Wintrobe, 1985). Osler rejected Pepper's idea that PA was a form of pseudoleukaemia, but hypothesized instead that it was a reversion of the bone marrow to an embryonic state, although why he did not know. Osler's lack of attention to nomenclature allowed Ehrlich to name the ‘megaloblast’ and ‘normoblast’ in 1880.

The microscopical characters of the blood in this disease are worthy of your closest attention, as I know of no disease in which that remarkably constant histological element, the red blood corpuscle, undergoes such important modifications ’ (Osler, 1881b)

In Osler's clinical lecture on PA in 1881, he described the typical findings and course while reviewing the literature (Osler, 1881b). Although treatment ‘is not very satisfactory’, he recommended iron, arsenic, blood transfusion and even mentioned milk transfusion. None was effective, as he reported that ‘all of our Montreal cases have died’. The duration of the disease was 3–12 months with unusual cases lasting 3–5 years.

Frederick Henry & Osler (1886) reported on atrophy of the stomach with the clinical features of progressive PA. The patient was a 42-year-old man with symptoms of anaemia. Physical examination showed the skin to have the peculiar yellowish pallor, which by now Osler stated was almost pathognomonic of PA, along with pale mucous membranes that appeared bloodless. The red blood cell count was 790 000 per mm3 with oval macrocytes, some of which were four times normal size. The patient died 6 months later with a red cell count of 315 000. Osler reported that the blood platelets were also reduced. Autopsy showed pallor of the skin and all organs, and bone marrow hyperplasia. The stomach had a grossly thin mucous membrane in the fundus and small nodular projections. A drawing from the Henry and Osler paper shows gastric atrophy involving all layers of the stomach membrane. A prominent feature in the drawing is the round cells (lymphocytes), which infiltrated all the layers of the stomach.

The authors agreed with the previous suggestions by Flint and Fenwick, and concluded that ‘certain of the cases of progressive pernicious anaemia depend upon profound alterations in the gastric tubules’.

In the seventh edition of The Principles and Practice of Medicine, the last that he revised personally, Osler commented that his PA series consisted of 81 cases, 36 over the age of 50 years, and the disease was more common in males (Osler, 1909a). Osler distinguished Addisonian PA from the anaemia of pregnancy and postpartum state. Despite his previous paper with Henry, he suggested that those cases with gastric atrophy might be separate from idiopathic Addisonian PA. He cited strong evidence for haemolysis, which, together with the pallor, accounted for the lemon tint of the skin. He said that nucleated red cells were almost always present, normoblasts and megaloblasts, and gave Ehrlich credit for these terms. The blood ‘plates’ were generally reduced. He described neurological findings with the numbness of the feet generally greater than that of the hands, sometimes accompanied by pain, and that the neurological findings correlated with posterolateral sclerosis of the spinal cord. Of his 81 cases, 27 died with an average duration of 1 year. Three of Osler's patients recovered, and he cited occasional reports of recovery from the literature. ‘The history is not one of progressing advance but of alternate periods of gain and loss’. For many years, Osler suggested arsenic for the treatment of anaemia (Osler, 1886b). Although there was little evidence that it helped in PA, as late as 1919, he included arsenic (‘in which I still have faith’) in his treatment recommendations (Osler, 1919).

In the decade after Osler's death, the landmark studies of liver therapy by Minot and Murphy provided successful treatment for a previously fatal disease, and those on intrinsic factor by Castle clarified the pathophysiology of PA (Castle, 1980). Minot had become interested in the possible role of diet in PA, based on G. H. Whipple's results in bled dogs. About the same time, Homer Wright taught Minot how to identify reticulocytes. Another of the most important therapeutic advances in medicine occurred shortly after Osler died: the discovery of insulin by Banting and Best in Macleod's laboratory in Toronto during 1921–2. Coincidentally, Minot became ill with severe diabetes mellitus in late 1921 (Rackemann, 1956). By January 1923, Elliott Joslin had obtained insulin for Minot, which controlled his diabetes. He returned to work and remained on insulin for the rest of his life. In May 1926, Minot and Murphy presented their results to the Association of American Physicians: 45 PA patients had been given up to half a pound of cooked beef liver per day, daily reticulocyte counts were done, and the anaemia improved in all. Their Nobel Prize-winning article describing these patients appeared in JAMA that August (Minot & Murphy, 1926). The authors cited Osler who had written that some patients improved with ‘change of air and a better diet…’– nothing was mentioned about his previous scientific contributions to the study of the disease.

Although Osler made significant contributions to the study of PA (Table III), they have not received much recognition in the history of the disorder (Castle, 1980; Hoffbrand & Herbert, 1999).

Table III.  Osler's studies on pernicious anaemia (PA).
Gardner & Osler (1877): probably the first case in which clinical, haematological and pathological descriptions fit modern definition
Osler described microscopic blood picture – macroovalocytes and large nucleated red cells with abnormal chromatin, later named megaloblasts by Ehrlich
Osler recognized intense bone marrow hyperplasia, but rejected the concept of ‘pseudoleukaemia’
Osler documented gastric atrophy and agreed with earlier suggestions by Flint and Fenwick that this finding was related to aetiology of PA
Recognized that spontaneous remissions, usually transient, occurred in some patients

Polycythaemia vera (Osler–Vaquez disease)

  1. Top of page
  2. Osler's role in the development of internal medicine
  3. Osler's Contribution to Haematology ()
  4. Osler and the microscope
  5. Platelets
  6. Pernicious anaemia (PA)
  7. Polycythaemia vera (Osler–Vaquez disease)
  8. Malaria
  9. Splenic anaemia
  10. Hereditary haemorrhagic telangiectasia (HHT) (Osler–Weber–Rendu disease)
  11. Other conditions
  12. Acknowledgments
  13. Note added in Proof
  14. References

Plethora had been recognized by Hippocrates and Maimonides, but the term polycythaemia vera (PV) entered the medical literature only about a century ago. Osler's role in defining and popularizing this disorder was one of his most important clinical contributions (Stone, 2001).

Louis Henri Vaquez described cyanotic polycythaemia in 1892 (Vaquez, 1892). The first patient was a 40-year-old man with cyanosis, dilated veins, facial plethora and hepatosplenomegaly. Cardiac auscultatory signs and oedema were absent. Examination of the blood showed 8 900 000 red cells. Despite the absence of auscultatory signs, Vaquez initially attributed the condition to congenital heart disease. The patient died the following year of acute tuberculosis. Autopsy confirmed splenic (1800 g) and hepatic (2800 g) enlargement. Cardiac disease was absent.

In 1903, Osler spoke on ‘Chronic cyanosis with polycythaemia and an enlarged spleen: a new clinical entity’ at a meeting of the Association of American Physicians. His report was subsequently published in the American Journal of the Medical Sciences (Osler, 1903a) (Fig 6). Osler's paper described four patients with chronic cyanosis and polycythaemia (polyglobulism), two of whom had enlarged spleens. He cited Vaquez's case and four others from the literature.

image

Figure 6. Osler's first publication on polycythaemia vera. He commented on Vaquez's case reported in 1892 and later suggested that the disorder be named ‘Vaquez's disease' (Stone, 2001).

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Osler's first patient was a 44-year-old physician seen in 1901, at which time his red count was 9 952 000 per mm3 and haemoglobin 120%. Several determinations were made, as it was thought that there might have been a counting error. Evidence for heart disease and emphysema was absent. Osler discussed the ‘torpor, mental and physical’ which characterized these patients and noted that the first patient looked ‘red as a rose and bursting with blood on a hot summer day’ while in winter, he became as ‘blue as indigo’. He commented on the occurrence of vascular disease, erythromelalgia and hypertension as well as intense bone marrow hyperplasia. He did not recognize the frequent association with leucocytosis or thrombocytosis. Osler favoured the term erythraemia and made an analogy with leukaemia: oversupply without corresponding demand. He recommended treatment with repeated bleedings and possibly inhalation of oxygen and splenic irradiation.

Osler distinguished polycythaemia (polyglobulism) of two types. One was relative and caused by haemoconcentration; the other was true, with persistent elevation of the red count. Secondary causes for the latter included high altitude, congenital heart disease and emphysema, but red cell counts in patients with these conditions typically were not as high as in Osler's cases. Osler proposed that the patients he described represented a new clinical entity and concluded by stating that the ‘clinical picture is certainly very distinctive; the symptoms, however, are somewhat indefinite, and the pathology quite obscure’. Osler (1904h) contrasted the findings in his patients with those in patients with splenic tuberculosis.

Osler's ‘Clinical lecture on erythraemia’ was delivered at the Radcliffe Infirmary (Osler, 1908c), Oxford, and began with the following words:

Gentlemen, It is interesting to follow the stages in the recognition of a new disease. Very rarely does it happen that at all points the description is so complete as at once to gain universal acceptance. Albuminous urine and its association with dropsy had been noted before Bright studied the changes in the kidneys and drew with a master hand the picture of the disease which we now know so well. Complete as was Addison's monograph it took a good many years before we recognized fully the relation of the suprarenal bodies to the disease that now bears his name. The original description of the simultaneous disease of the lymph glands and spleen by the distinguished old Quaker physician, Hodgkin, had not attracted any more attention than had his equally remarkable contribution on insufficiency of the aortic valves (which antedated by several years Corrigan's account), until Wilks, the “grand old man” today of British medicine, drew attention to the condition. And so it was with myxoedema, which was well known for years in England before our continental brethren recognized its existence. First a case here and there is reported as something unusual; in a year or two someone collects them and emphasizes the clinical features and perhaps names the disease. Then in rapid succession new cases are reported and we are surprised to find that it is by no means uncommon. This has been the history of a very remarkable malady of which the patient before you is the subject.'

Osler's lecture on erythraemia provided a comprehensive clinical picture of the disorder (Wintrobe, 1949). The presentation was a classic example of Osler's method of bedside teaching – the integration of clinical observation and laboratory findings with pathophysiological concepts (Robb-Smith, 1981). In the seventh edition of his textbook, Osler (1909b) described the condition as ‘splenomegalic polycythaemia with cyanosis (Vaquez's disease)'. The chronic disorder was associated with red blood cell counts of 9–13 million/mm3. Headache, giddiness and constipation were common symptoms. Patients were said to have a brick-red colour or, when cold, marked cyanosis. At autopsy, extreme bone marrow hyperplasia was found. Osler suggested that the disorder was the red cell counterpart of leukaemia.

Parkes Weber (1908) recognized the frequent elevation of the white blood count in peripheral blood and remarked that, ‘the increased activity of the bone marrow is in its results practically equivalent to a gradual persistent transfusion of blood into the vessels’. By 1912, 181 cases were cited by Lucas (1912), who pointed out that, although a few cases of the disease had been reported, it was not until Osler's papers that the condition was widely recognized. Minot & Buckman (1923) considered PV to be a neoplasm closely related to chronic myelogenous leukaemia. They called attention to the elevated platelet counts and increased marrow megakaryocytes that were prominent features of the disorder. Minot and Buckman also described the late occurrence of anaemia and massive splenomegaly in some patients. Dameshek (1951) incorporated PV into his concept of myeloproliferative disorders. Adamson et al (1976) provided evidence that PV was a clonal stem cell disorder.

Malaria

  1. Top of page
  2. Osler's role in the development of internal medicine
  3. Osler's Contribution to Haematology ()
  4. Osler and the microscope
  5. Platelets
  6. Pernicious anaemia (PA)
  7. Polycythaemia vera (Osler–Vaquez disease)
  8. Malaria
  9. Splenic anaemia
  10. Hereditary haemorrhagic telangiectasia (HHT) (Osler–Weber–Rendu disease)
  11. Other conditions
  12. Acknowledgments
  13. Note added in Proof
  14. References

Laveran's description of pigmented inclusions in the erythrocytes of patients with malaria was initially reported in 1880 and followed by a monograph 4 years later. At the first meeting of the Association of American Physicians in 1886, Osler (‘speaking out of the fulness of my ignorance’) was sceptical about Laveran's findings despite supportive findings from others (Osler, 1889a; Robb-Smith, 1981). Osler's view was based on inspection of fresh preparations rather than stained fixed blood smears, which the other physicians had used. After the meeting, Osler returned to Philadelphia and, with George Dock, inspected both fresh and stained blood smears. They were promptly convinced of the validity of Laveran's description of the Plasmodium in the blood of patients with malaria. Osler rapidly sent communications to several journals in which he admitted he had been wrong about Laveran's findings. (Osler, 1886c, 1887). Later he remarked, ‘Happy those who had agility and wit sufficient for the somersault!’ (Osler, 1895a). As with PV, Osler's influence proved important in the acceptance of Laveran's work. Moreover, in Philadelphia and in Baltimore, blood films were examined in all cases of fever and then routinely (Osler, 1889b).

One swallow does not make a summer, but one tophus makes gout and one crescent malaria ’ (Bean & Bean, 1961b)

Splenic anaemia

  1. Top of page
  2. Osler's role in the development of internal medicine
  3. Osler's Contribution to Haematology ()
  4. Osler and the microscope
  5. Platelets
  6. Pernicious anaemia (PA)
  7. Polycythaemia vera (Osler–Vaquez disease)
  8. Malaria
  9. Splenic anaemia
  10. Hereditary haemorrhagic telangiectasia (HHT) (Osler–Weber–Rendu disease)
  11. Other conditions
  12. Acknowledgments
  13. Note added in Proof
  14. References

Osler wrote several papers on the perplexing relationship between splenic enlargement and anaemia between 1882 and 1914 (Osler, 1882b, 1899a, 1900a, 1902, 1908d). He believed these cases were characterized by (1) splenomegaly, often for many years; (2) secondary anaemia and leucopenia; and (3) a late stage with cirrhosis, jaundice and ascites. He recognized that these findings existed in a number of distinct conditions (Osler, 1902, 1908d).

The diagnosis of conditions associated with enlargement of the spleen is important, but somewhat complicated, owing to the number of lacunae in our knowledge of the aetiology of the various forms, and their relation to one another ’ (Osler, 1899a)

Hereditary haemorrhagic telangiectasia (HHT) (Osler–Weber–Rendu disease)

  1. Top of page
  2. Osler's role in the development of internal medicine
  3. Osler's Contribution to Haematology ()
  4. Osler and the microscope
  5. Platelets
  6. Pernicious anaemia (PA)
  7. Polycythaemia vera (Osler–Vaquez disease)
  8. Malaria
  9. Splenic anaemia
  10. Hereditary haemorrhagic telangiectasia (HHT) (Osler–Weber–Rendu disease)
  11. Other conditions
  12. Acknowledgments
  13. Note added in Proof
  14. References

In 1901, Osler described three patients with recurrent epistaxis and multiple telangiectases (Osler, 1901a). He mentioned Rendu's report of a similar patient 5 years earlier. Two of Osler's patients were brothers; a total of seven family members were affected over three generations. Patients with hereditary telangiectasia were clearly distinguished from those with haemophilia. By 1907, Osler had studied a second family with four affected members and found six other kindreds in the literature (Osler, 1907b). The disorder is mentioned in the sections on ‘Epistaxis’ and ‘Hemophilia’ in the seventh edition of his textbook.

In the great majority of the cases the bleeding is from the nose, and has the usual character of epistaxis. In other instances the blood comes from the spots on the lips, the tongue, gums, and mucous membrane of the palate. Only in a few instances has the bleeding been from the spots on the skin… ’ (Osler, 1907b)

Other conditions

  1. Top of page
  2. Osler's role in the development of internal medicine
  3. Osler's Contribution to Haematology ()
  4. Osler and the microscope
  5. Platelets
  6. Pernicious anaemia (PA)
  7. Polycythaemia vera (Osler–Vaquez disease)
  8. Malaria
  9. Splenic anaemia
  10. Hereditary haemorrhagic telangiectasia (HHT) (Osler–Weber–Rendu disease)
  11. Other conditions
  12. Acknowledgments
  13. Note added in Proof
  14. References

Osler wrote about many haematological and oncological topics (Golden & Roland, 1988). He contributed the chapter on blood diseases for Pepper's System of Practical Medicine in 1885 (Osler, 1885), with lucid descriptions of leukaemia, Hodgkin's disease and haemophilia. The section on blood diseases in the first edition of The Principles and Practice (Osler, 1892b) consisted of 25 pages on anaemia, leukaemia and Hodgkin's disease. This section was expanded to 41 pages in the seventh edition (Osler, 1909a) when discussions of purpura, haemophilia, scurvy, status lymphaticus and the spleen were included with blood disorders. In the first edition of his textbook, Osler remarked that Bence Jones protein was ‘not of any practical importance’ but, in the seventh edition, acknowledged its value in the diagnosis of myeloma; by then 35–40 cases had been reported (Stone, 1998). He described the peculiar thermal properties of the unusual urinary protein. Osler also wrote about amyloidosis and haemochromatosis. The amyloid cases were of the secondary (reactive) type occurring in patients with tuberculosis or syphilis. Osler questioned whether amyloidosis might be curable and noted that regression of hepatosplenomegaly was sometimes seen. Prophetically, he also suggested that there might be different types of amyloid (Osler, 1886d). He was a student of abdominal tumours, especially cancer of the stomach, and often supported the role of surgery. The close co-operation between Osler and Halsted at Johns Hopkins was perhaps one of the earliest examples of multidisciplinary management, which later proved so valuable in oncology.

In a series of three papers on the visceral manifestations of the erythema group of skin diseases, Osler recognized and emphasized that patients with skin findings had similar lesions in the internal organs (Osler, 1895b, 1900b, 1903b). A review of these studies half a century later indicated that he had brilliantly ‘constructed the framework for the clinical picture’ of disseminated lupus erythematosus (Tumulty & Harvey, 1949).

In 1906, Osler was shown a patient with a 10-year history of a peculiar telangiectatic condition – dark red spots were present on the trunk and extremities that blanched with pressure and, after rubbing, turned red with urticaria. Excellent photographs were included in the article (Osler, 1907c). The patient's skin was unchanged 1 year later. Although no biopsy was obtained, it is likely that Osler's patient had adult urticaria pigmentosa (mastocytosis) (Robb-Smith, 1981).

Osler made another contribution, which surely surpassed all the others. Ever the clinician–microscopist, he introduced clinical diagnostic microscopy into North American medicine (Osler, 1899b). Laboratory observations were an extension of those made at the bedside (Pratt, 1949). Proficiency with the microscope was considered as important as accurate auscultation (Conn, 1985). At Hopkins, Thayer was probably the first in the United States to use Ehrlich's method for staining blood cells in 1891. John Auer's description of the rod-shaped cytoplasmic inclusions occurring in acute leukaemia was reported in 1906. Two textbooks on laboratory procedures, both entitled Clinical Diagnosis, emanated from Hopkins in 1896 (Simon, 1896) and 1906 (Emerson, 1906). Figure 7 shows the Clinical Microscopy Laboratory at Johns Hopkins, immediately adjacent to the wards, with medical students and house officers studying their patients' blood (Osler, 1901b). Osler brought the microscope to the clinic, enabling physicians to arrive at accurate diagnoses and rational therapy for patients. The impact of clinical microscopy also had an important role in helping to define the aetiology and pathogenesis of blood disorders.

image

Figure 7. The Clinical Microscopy Laboratory at Johns Hopkins. Adjacent to the wards, it accommodated 110 students. Osler remarked, ‘Conducted properly, with a protracted course and ample material, this class becomes one of the most popular, as it certainly is one of the most useful, in the curriculum’ (Osler, 1901b).

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William Osler's contributions to haematology, although only a small portion of his massive legacy, were indeed substantial. As a young clinician–investigator, his studies on platelets preceded those of Bizzozero, and his description of the megaloblast antedated Ehrlich. In both cases, the other workers named the respective cellular element. Later in his career, Osler's incisive clinical descriptions of PV and HHT led to his name being attached to both disorders. One is reminded of Osler's own words: ‘In science the credit goes to the man who convinces the world, not to the man to whom the idea first occurs’ (Bean & Bean, 1961c).

Dr Max Wintrobe, who took over the Clinical Microscopy Laboratory at Johns Hopkins a generation after Osler left Baltimore later referred to him as ‘the first American haematologist’ (Wintrobe, 1985).

The best doctor, like the successful general, is the one who makes the fewest mistakes ’ (Osler, 1911).

Acknowledgments

  1. Top of page
  2. Osler's role in the development of internal medicine
  3. Osler's Contribution to Haematology ()
  4. Osler and the microscope
  5. Platelets
  6. Pernicious anaemia (PA)
  7. Polycythaemia vera (Osler–Vaquez disease)
  8. Malaria
  9. Splenic anaemia
  10. Hereditary haemorrhagic telangiectasia (HHT) (Osler–Weber–Rendu disease)
  11. Other conditions
  12. Acknowledgments
  13. Note added in Proof
  14. References

Presented in part at the 22nd, 28th and 32nd meetings of the American Osler Society (1992, San Diego, CA; 1998, Toronto, Ontario, Canada; 2002, Kansas City, MO). This study was supported in part by the Edward and Ruth Wilkof Foundation, the Robert Schanbaum Memorial Fund and the James E. Nauss Cancer Research Fund. I thank Jill Stone for editorial assistance and support. Ms. Linda Miller provided expert help with manuscript preparation.

Note added in Proof

  1. Top of page
  2. Osler's role in the development of internal medicine
  3. Osler's Contribution to Haematology ()
  4. Osler and the microscope
  5. Platelets
  6. Pernicious anaemia (PA)
  7. Polycythaemia vera (Osler–Vaquez disease)
  8. Malaria
  9. Splenic anaemia
  10. Hereditary haemorrhagic telangiectasia (HHT) (Osler–Weber–Rendu disease)
  11. Other conditions
  12. Acknowledgments
  13. Note added in Proof
  14. References

Dorothy Reed, a Johns Hopkins medical graduate and house officer, performed her classic studies on Hodgkin's disease as a Fellow in Pathology (Reed DM. 1902. On the pathological changes in Hodgkin's disease, with especial reference to its relation to tuberculosis. Johns Hopkins Hosp. Rep. 10: 133–196). In her autobiography, she stated that Osler was the greatest teacher she had ever known (Bliss, 1999).

References

  1. Top of page
  2. Osler's role in the development of internal medicine
  3. Osler's Contribution to Haematology ()
  4. Osler and the microscope
  5. Platelets
  6. Pernicious anaemia (PA)
  7. Polycythaemia vera (Osler–Vaquez disease)
  8. Malaria
  9. Splenic anaemia
  10. Hereditary haemorrhagic telangiectasia (HHT) (Osler–Weber–Rendu disease)
  11. Other conditions
  12. Acknowledgments
  13. Note added in Proof
  14. References
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  • Minot, G.R. & Murphy, W.P. (1926) Treatment of pernicious anemia by a special diet. Journal of the American Medical Association, 87, 470476.
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  • Nation, E.F. (ed.) (1987) Men and Books, pp. 167. Sacrum Press, Durham, NC.
  • Nation, E.F. & McGovern, J.P. (eds) (1980) Student and Chief. The Osler–Camac Correspondence, pp. 1131. Castle Press, Pasadena, CA.
  • Nation, E.F., Roland, C.G. & McGovern, J.P. (1976) An Annotated Checklist of Osleriana, pp. 1298. Kent State University Press, Kent, OH.
  • Osler Memorial Issue (1949) Bulletin of Johns Hopkins Hospital, 85, 1114.
  • Osler, W. (1869) Christmas and the microscope. Hardwicke's Science-Gossip: an Illustrated Medium of Interchange and Gossip for Students and Lovers of Nature, 5, 44.
  • Osler, W. (1871) Carcinoma mammae. Removal by excision. Canadian Medical Journal, 8, 107109.
  • Osler, W. (1874) An account of certain organisms occurring in the liquor sanguinis. Proceedings of the Royal Society of London, 22, 391398.
  • Osler, W. (1881a) Ulcerative endocarditis. Transactions of the New York Pathological Society, 4, 29.
  • Osler, W. (1881b) Clinical lecture on idiopathic or pernicious anemia. Canadian Journal of Medical Science, 6, 135141.
  • Osler, W. (1882a) Bizzozero's new (?) blood element and its relation to thrombus formation. Medical News, 40, 250.
  • Osler, W. (1882b) Clinical notes on haematemesis in chronic splenic tumors. Canada Medical and Surgical Journal, 11, 267270.
  • Osler, W. (1883) The third corpuscle of the blood. Medical News, 43, 701702.
  • Osler, W. (1885) Diseases of the blood and blood-glandular system. In: A System of Practical Medicine (ed. by W, Pepper), pp. iii and 882 – 950. Lea & Brothers, Philadelphia.
  • Osler, W. (1886a) Cartwright lectures. On certain problems in the physiology of the blood corpuscles. Medical News, April 3, 10, 17.
  • Osler, W. (1886b) On the use of arsenic in certain forms of anaemia. The Therapeutic Gazette, 3rd Series, II, 741746.
  • Osler, W. (1886c) The malarial germ of Laveran (unsigned editorial). Medical News, 49, 265266.
  • Osler, W. (1886d) Is amyloid degeneration curable? (unsigned editorial). Medical News, 48, 125.
  • Osler, W. (1887) An address on the hematozoa of malaria. Transactions of the Pathological Society of Philadelphia, 13, 255276; also British Medical Journal, I, 556 – 562.
  • Osler, W. (1889a) On phagocytes. Medical News, 54, 421425.
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  • Osler, W. (1895a) The practical value of Laveran's discoveries. Medical News, 67, 561564.
  • Osler, W. (1895b) On the visceral complications of erythema exudativum multiforme. American Journal of the Medical Sciences, 110, 629646.
  • Osler, W. (1899a) Chronic splenic enlargement with recurring gastro-intestinal haemorrhages. Edinburgh Medical Journal, 5, 441453.
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  • Osler, W. (1900a) On splenic anaemia. American Journal of the Medical Sciences, 119, 5473.
  • Osler, W. (1900b) The visceral lesions of the erythema group. British Journal of Dermatology, 12, 227245.
  • Osler, W. (1901a) On a family form of recurring epistaxis, associated with multiple telangiectases of the skin and mucous membranes. Johns Hopkins Hospital Bulletin, 12, 333337.
  • Osler, W. (1901b) The natural method of teaching the subject of medicine. Journal of the American Medical Association, 36, 16731679.
  • Osler, W. (1902) Anaemia splenica. Transactions of the Association of American Physicians, 17, 429461.
  • Osler, W. (1903a) Chronic cyanosis with polycythaemia and enlarged spleen: a new clinical entity. American Journal of Medical Science, 126, 187201.
  • Osler, W. (1903b) On the visceral manifestations of the erythema group of skin diseases. Transactions of the Association of American Physicians, 18, 599624.
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  • Osler, W. (1904d) On the educational value of the medical society. In: Aequanimitas with Other Addresses to Medical Students, Nurses and Practitioners of Medicine, pp. 343362. Blakiston, Philadelphia.
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  • Osler, W. (1904g) Books and men. In: Aequanimitas with Other Addresses to Medical Students, Nurses and Practitioners of Medicine, pp. 217225. Blakiston, Philadelphia.
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  • Osler, W. (1905) Resumé of the history of the blood platelets. Johns Hopkins Hospital Bulletin, 16, 200201.
  • Osler, W. (1907a) The reserves of life. St Mary's Hospital Gazette, 13, 9598.
  • Osler, W. (1907b) On multiple hereditary telangiectases with recurring haemorrhages. Quarterly Journal of Medicine, I, 5358.
  • Osler, W. (1907c) On telangiectasis circumscripta universalis. Johns Hopkins Hospital Bulletin, 18, 401403.
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  • Osler, W. (1908d) Splenic enlargements other than leukaemia. British Medical Journal, II, 11511154.
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