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William Prout: early 19th century physician-chemist.

In an age when the description of disease was often a mere catalog of symptoms, there were few medical men in the early 19th century who appreciated the usefulness of chemistry in the explanation and treatment of disease. Although investigations in the chemistry of disease were being carried out in the 1820s, 1830s, and 1840s, its application in routine diagnosis was not widespread. The work of several British physician-chemists--Rees (1), Bence Jones (2), and Marcet (3)--has been described in previous issues of this journal, and elsewhere by N.G. Coley (4-6) and F.W. Putnam (7). The subject of this article is William Prout (1785-1850) (Fig. 1).

Like many other 19th century physicians of humble origins, Prout's earlier education was almost negligible and was over by the age of 13. By the age of 17, aware of his own educational deficiencies, he pursued a pattern of systematic learning, first in a private academy and then in a classical seminary. He was encouraged to study medicine at the University of Edinburgh. (Oxford and Cambridge were outside his social status.) Thus, in 1808, at age 23, he enrolled at Edinburgh. He was graduated MD in June 1811. He next "walked the wards" of the United Hospitals of St. Thomas's and Guy's to obtain practical experience and passed the examination for licentiate of the Royal College of Physicians in December 1812. Prout was admitted as a Fellow of the Royal College of Physicians in 1829; he also served two terms as vice-president of the Medical Society of London (8, 9).

Prout was an early riser who did some of his scientific work before he breakfasted at 7 in the morning. The remainder of the day was devoted to his patients. Besides his extensive town practice in urinary disorders, packages arrived daily from the country for analysis. Prout was not primarily a clinician and had a reputation for being lax in charging his patients. Most of his analyses and scientific experiments were made with ingenious apparatus of his own design, for which he spared no expense in construction. This seeming unconcern about money kept him from the financial success of many of his colleagues at a time when great fortunes could be made in the practice of medicine (9, 10).

During the first half of the 19th century, clinical chemistry emerged from applications of chemistry to medical diagnosis. The discoveries of new substances in the healthy and diseased body that accompanied the beginning of scientific medical research, and the development of organic and physiological chemistry, spawned a wave of interest in clinical chemistry as a recognizable identity in the late 1830s and 1840s. There followed a systematic search for pathologic changes in the chemical composition of body fluids to guide medical diagnosis, follow the course of the disease, and control therapy. A search for chemical explanations for physiologic phenomena became a major preoccupation of leading scientists during the 19th century.


Preparation and Analysis of Urea

In seeking the cause of urinary calculi, Antoine Francois Fourcroy (1755-1809) and Nicholas Vauquelin (1763-1829) investigated the composition of urine and developed procedures for the isolation and study of urea. There had been earlier descriptions. Johannes van Helmont (1577-1644) (11) had isolated two salts from urine: one was sea salt, which he said was taken with food; the other, salt of urine, was of different crystalline form and, unlike the sea salt, was volatile when heated (probably urea). Sometime before 1727, Hermann Boerhaave (1668-1738), the renowned Dutch physician-chemist, described a crystalline residue obtained from urine that he had concentrated by heating, filtering, washing, and evaporating, which he called "the native salt of urine" and which he distinguished from sea salt (sodium chloride), also present in urine. Hilaire Marin Rouelle (1718-1779) in 1773 prepared an impure urea from the alcoholic extract of an evaporated urine residue. Rouelle called it matiere savonneuse (soapy matter). In England in 1797, William Cruickshank (1745-1800) added concentrated nitric acid to evaporated urine and obtained crystalline urea nitrate.

In 1799 Fourcroy and Vauquelin prepared a nearly pure urea, which they named uree (12). They prepared a much purer urea in 1808 when the sparingly soluble urea nitrate was neutralized by aqueous potassium carbonate. After evaporation to dryness, the residue was extracted with alcohol to separate the urea from the potassium nitrate. Evaporation of the alcoholic solution yielded crystals of urea. Because an aqueous solution of urea decomposes on boiling to carbonic acid, acetic acid, and ammonia, they speculated that ammonia-containing calculi might be formed by the partial fermentation of urea in the bladder.

Finally in 1817, a pure urea product was isolated, its properties, appearance, and chemical reactions were described, and its analysis was accurately determined by William Prout (first exhibited, he said, at some lectures he had given 3 years earlier). Prout introduced a purification step with animal charcoal before extraction with boiling alcohol. This became the textbook method of choice for the preparation of urea. Prout's analysis (by combustion) of the percentage composition of the component elements of urea was virtually identical with the values calculated from what we now know to be its formula (13, 14).

Prout used Gay-Lussac's method (1816) of completely oxidizing the urea with black oxide of copper, which at a suitable temperature readily gives up its oxygen to hydrogen and carbon but not to nitrogen. The nitrogen, uncombined, was collected in a calibrated gasometer. Prout calibrated his weights with platinum standards, and all materials to be analyzed were dried over sulfuric acid in a vacuum apparatus of his own design, at ~200 [degrees]F (13). Prout was meticulous in his analytical techniques and strove for purity of reagents and organic substances.

Years later, Prout acknowledged that "from its composition I was satisfied that it might be formed artificially. I made numerous attempts to form it, but did not succeed; and the honour of forming the first organic product artificially is due to Wohler". Prout also claimed to have found urea (or a substance having most of its properties) in blood in 1816. Believing it was accidental, he did not pursue the inquiry, but made a note of it (15).

Chemical science had a slow and difficult beginning. Nearly a century elapsed between the first isolation of urea by Boerhaave and the preparation and analysis of the first pure specimen by Prout. Only a few years later, in 1828, the laboratory synthesis of urea by Friedrich Wohler (1800-1882) played an important role in stimulating further synthesis in organic chemistry.

Prout's Hypothesis

Prout's name is associated with the two hypotheses of integral atomic weights and the unity of matter, i.e., the atomic weights of all chemical elements are whole-number multiples of the atomic weight of hydrogen. He suggested that hydrogen might be the primary matter from which all other "elements" were formed. This was expressed in two papers in the Annals of Philosophy (1815, 1816). They were titled "The Relationship between Specific Gravities of Bodies in Their Gaseous State, and the Weights of Their Atoms". The papers dealt with the calculation of the specific gravities (relative densities) of the elements from the published data of other chemists. He derived an excellent value for hydrogen, which owing to its light weight had been very difficult to determine accurately by experiment.

"Prout's Hypothesis" was perhaps his most widely known contribution to chemistry. It stimulated discussion and improvement of analysis and forced interest in the determination of accurate atomic weights, and thereby in the atomic theory, and in a search for a system of classification of the elements (16, 17). Published anonymously at first, Prout quickly identified himself as the author when he found that his ideas had been accepted by the eminent chemist Thomas Thomson, founder of the Annals of Philosophy. Prout was content to leave the promotion of his speculation to the status of a law to Thomson while he himself returned to perfecting techniques of organic analysis.

Analysis of Urine

Entering the 19th century and the era of atomic weights and atomic theory, chemistry began to disengage from its qualitative and descriptive character in the previous century when applications of chemistry to medicine were directed to the understanding of disease rather than to its relief. "Chemistry being a science of observation", Prout looked forward to the time "when chemistry shall be brought more under the control of the laws of quantity ..." (18). To those scientists known as vitalists, it was inconceivable that bodily functions could be explained by chemistry. They believed that the composition and workings of the body required a study of the vital functions, and they denied chemistry a role in physiology. Prout was an early and consistent advocate of the benefits to be derived from the application of chemistry to physiology in the treatment of disease (8). He also favored the study of physics and chemistry by medical students. One of Prout's admirers was Henry Bence Jones (1813-1873), who in 1850 credited him with being first to make the connection between chemistry and medical practice (19).

In 1814 Prout advertised a course of evening lectures on animal chemistry in his home. The topics were respiration and urine chemistry. Urine was subjected to systematic and scientific examination by Prout. His major work, An Inquiry Into the Nature and Treatment of Gravel, Calculus, and Other Diseases Connected with a Deranged Operation of the Urinary Organs (1821), was very popular and helped establish his reputation in Great Britain and Europe as one of Britain's distinguished physiological chemists. Prout's goal was to establish a coherent connection between the chemical processes of metabolism and excretion, as manifest in the urine, and the observed changes in the patient's clinical status.

By 1825, when the second edition of his book was published, now renamed An Inquiry Into the Nature and Treatment of Diabetes, Calculus, and Other Affections of The Urinary Organs, most of our present-day knowledge of the composition of urinary stones had been discovered. This book is one of the earliest to contain a list of "Tests, Apparatus, &c. required in making Experiments on the Urine", and this included litmus paper (blue and red), turmeric paper (plant extract exhibits color change from yellow to reddish-brown, and violet on drying, and is a test for alkalinity), a specific gravity bottle or a small portable hydrometer that Prout designed, blowpipe, forceps, two small discs of plate glass for discriminating pus from mucus, and a watch glass for detecting an excess of urea on addition of nitric acid. "These, with one or two small test tubes, and small stoppered phials, containing solutions of pure ammonia, potash, and nitric acid, can be readily packed into a small portable case, or pocket book, and will be sufficient, by the aid of a common taper or candle, to perform all the experiments on the urine, and urinary productions, that are commonly necessary in a practical point of view" (20). Alexander Marcet had described a portable chemical kit in 1817 and showed a line drawing of its components (3). Barely a year after Prout's list of tests and apparatus, Richard Bright's (1789-1858) studies of renal disease would add a spoon to this portable laboratory, for revealing the presence of albumin in heated urine.

Prout's routine for testing urine began with the 24-h volume, the color, and the transparency. Some of the immaginative notions of the uroscopists of the past were still in evidence here. The belief persisted that the urine's volume, color, and appearance were indicative of certain personality traits and were characteristic of particular diseases. Specific gravity was measured and, if [greater than or equal to]1.030, was considered diagnostic of diabetes. The reaction of urine, known to normally be acid, was taken with litmus paper. Albuminous urine (protein) was detected by heat coagulation, and bile by the yellow staining of linen. Sugar in the urine was still recognized by taste--there was no other test--and was "not found in the blood even of individuals labouring under diabetes, in whose urine it exists in the greatest abundance; ...". An excess of urea--regarded as abnormal but of vague significance--was inferred from the length of time for crystallization to occur when nitric acid was added to the urine on a watch glass. Prout claimed that in diabetes and some other diseases of the urine, very little urea is sometimes present. The color and appearance of any sediment settling out on standing were noted, but no microscopic examination was made (21). Some of the tests may have been crude, but they were chemical tests.

Prout's book appeared in five editions and underwent several name changes, appearing finally in 1848 as On the Nature and Treatment of Stomach and Renal Diseases; Being an Inquiry Into the Connexion of Diabetes, Calculus, and Other Affections of the Kidney and Bladder, with Indigestion. As edition followed edition, even contemporary reviewers criticized Prout for not examining and explaining some of the theoretical issues involved in physiology. Seeking to avoid controversy, he would settle these points with a strong conviction that almost appears as dogmatism. His inertia and conservatism were sharply criticized by The Lancet (22).

The book's lack of chemical formulae, which had become almost universally adopted in the 1830s but which Prout dismissed as unphilosophical expedients because they did not represent true compositions, and his omission of discoveries and advances made on the Continent showed an inability to keep up with the newer developments in chemistry and physiology and led to rapid replacement by other texts, notably that of Golding Bird (1814-1854) (23, 24). Prout's progressively worsening deafness since youth was a contributing factor. It reduced his personal contacts with other scientists, which made it difficult to keep up with the newer discoveries and advances in chemistry and physiology on the Continent. When, after 1830, his hearing loss became complete he withdrew from scientific society. Much of Prout's research had foreshadowed that of Justus Liebig (1803-1873) and his school, but was soon eclipsed by their achievements in the 1830s and 1840s (8, 25). Prout never referred to the action of oxygen on tissues, whereas Liebig and Wohler based all their studies on the concept of tissue oxidation. He also ignored the discovery of pepsin and G.J. Mulder's (1802-1880) proteine.

Chemical Remedies

Unlike many physicians, Prout had no wonderful remedy to offer for urinary calculi; the only real solution was the knife, for "When a calculus is once formed, its further enlargement is probably a common chemical process, and will proceed whether the urine be healthy or not, for all urine naturally contains the ingredients most commonly met with in calculi" (26).

Prout was very skeptical of so-called chemical remedies because of the possibility of dangerous side effects and their potential for ultimately aggravating the disease. Because "the object of the chemical practitioner is at best ... to prevent the effects of disease rather than to remove it", he considered "chemical remedies as palliatives only", and attributed "their acknowledged good effects" to "their general than their chemical operation; ..." (26).

Prout, however, did have a chemical remedy. After iodine salts were found in certain marine life forms, it occurred to him that burnt sponge (a well-known remedy for goiter) might owe its properties to the presence of iodine. In 1816, after trying hydriodate of potash (potassium iodate) on himself in small doses and experiencing no ill effects, Prout suggested iodine treatment for goiter. This therapy was successfully adopted by Dr. John Elliotson (1791-1868) at St. Thomas's Hospital early in 1819 (27).

A Satisfactory Diet

In 1827, "On the Ultimate Composition of Simple Alimentary Substances, with Some Preliminary Remarks on the Analysis of Organized Bodies in General" (28) earned Prout the Copley Medal, the highest distinction of the Royal Society. In this publication, considered during Prout's life his most important paper, Prout reported on his researches on food. He was the first to classify alimentary principles (foodstuffs) into saccharinous (carbohydrates), oleaginous (fats), and albuminous (proteins). The main purpose of this paper was to describe an accurate procedure for the analysis of organic materials, for which he used very expensive equipment of his own design, and especially to determine the exact composition of these major divisions and the subsequent changes induced in them. Prout added water to his trio of foodstuffs and laid great stress on its role in assimilation. He urged that a satisfactory diet should include all four foodstuffs and be modelled on the great alimentary prototype--milk.

In 1831 Prout referred to the saccharinous group of foodstuffs as "hydrates of carbon" (29). However, Carl Schmidt (1822-1894) is generally credited with originating the term "carbohydrate" (kohlenhydrate) in 1844 for those sugars containing hydrogen and oxygen in the same ratio as in water (30).

Chemistry vs Physiology: The Case Against Vitalism

In his three Gulstonian lectures on "The Application of Chemistry to Physiology, Pathology, and Practice", at the Royal College of Physicians in 1831 (29), Prout complained that the physiologists paid too much attention to mechanical or even metaphysical explanations in biology, whereas for him biology called for the application of chemistry. Citing the lack of progress in animal chemistry, he attributed this to the inherent difficulty of the subject but also to the lack of understanding by the pure, i.e., inorganic, chemist of the unfamiliar field of biology. Prout's remedy for this lack of progress was for physiologists to become chemists (31). This was reminiscent of an earlier appeal in 1816 when he stated: "Chemistry, however, in the hands of the physiologist, who knows how to avail himself of its means, will, doubtless, prove one of the most powerful instruments he can possess; ...". Furthermore, cautioned Prout, "Organic substances should be compared with one another, and not with inorganic ones, with which they have little or no analogy". He advised the physiological chemist to pay attention only to what is actually observed and to avoid superfluous experiment and visionary hypothesis (32).

Prout's Gulstonian lectures got him embroiled in a running acrimonious debate with Wilson Philip in the pages of the London Medical Gazette (33). Philip, a physiologist and vitalist, could see no value in applying chemical methods and reasoning to the problems of physiology. Philip resented Prout's claim that almost no progress had been made in physiology in 20 years. Philip charged: "Chemistry, and the science of the vital functions, are of so different a nature, that if they be pursued with ardour, and without this nothing can be done in such subjects, the one will tend constantly to abstract the mind from, and perhaps in some degree to unfit it for, the other; ..." (34). By the 1840s, the vitalist Philip did a complete turnaround to Prout's viewpoint, even claiming that the nervous system was essentially chemical. Prout, on the other hand, despite his call for the application of chemistry to biology became more committed to vitalism, but avoided a new confrontation.

It always remained a shortcoming of Prout's scientific method to use lack of knowledge as an argument for vitalism. Prout believed that there exists "in all living organised bodies some power or agency, whose operation is altogether different from the operation of the common agencies of matter, and on which the peculiarities of organised bodies depend, ...". Of the various hypotheses explaining these differences, Prout favored that of "independent existing vital principles or 'agents,' superior to, and capable of controlling and directing, the forces operating in inorganic matters; on the presence and influence of which the phenomena of organisation and of life depend" (35). Despite these expressions of vitalism, Prout's application of chemistry to biology brought him criticism from vitalists.

A strong prejudice existed in those days among the leading physicians against chemical doctrines, and the quarrels that ensued among them were frequently virulent and vituperative. Personal antagonisms were aired in the medical journals, most notably The Lancet, whose founder and editor, Thomas Wakley (1795-1862), was adept at provoking dissension. The letters to the editor were often lengthy and frequently signed by a pseudonym. Accusations of bias or incompetence against individuals or institutions usually generated a response and counter-response, which went on from issue to issue and helped stimulate circulation of the journal.

The Acid of Gastric Juice

In 1824, William Prout showed that the acid of the gastric juice was hydrochloric acid. Gastric digestion had long been the subject of speculation and experimentation. Van Helmont discovered the significance of acid in gastric digestion, which up to that time and for long after was attributed to heat and trituration, but he reasoned that gastric digestion is not attributable to acidity as such, because neither vinegar nor lemon juice will digest food. He attributed digestion to a specific "vital acidity". Van Helmont gave his chemical concept of digestion a vitalistic identity by stating that the acid in the stomach is not the vital agent itself, but made its action possible (11).

The iatrochemical school that succeeded Van Helmont explained all body functions as being determined by chemical reactions without direction by any mystical or spiritual force. Gastric digestion was regarded as a chemical fermentation, with saliva playing an important initial role. With progressing mechanization of theoretical medicine in the early 18th century, the human organism was regarded as a machine and

digestion as a mechanical process subject to physical laws. Van Helmont's vitalistic doctrine of acid digestion was replaced by a theory of liquefaction resulting from agitation. The reasoning was that a chemical substance in the stomach capable of converting solid food, notably meat, into a fluid would also dissolve the fleshy wall of the stomach (36).

The iatromechanical theory of gastric digestion by agitation of the food with resulting liquefaction dominated until the latter half of the 18th century. A new line of investigation was opened by the French physicist, Rene de Reaumur (1683-1757), who persuaded a kite (a species of buzzard that easily disgorges what it does not digest) to swallow open-ended tubes containing food. His experiment in 1752 demonstrated the dissolving action of gastric fluid on the regurgitated foods.

These findings were extended by the Italian physiologist Lazzaro Spallanzani (1729-1799), who administered food samples in perforated metallic tubes to a large variety of animals. The containers were removed by regurgitation or by sacrificing the animal, and the contents were examined for weight loss and other changes. Spallanzani experimented on himself with food swallowed in linen bags, which he recovered for analysis. He also obtained samples of his own gastric fluid by regurgitating on an empty stomach. In 1782 he studied the solvent action of gastric fluid on foodstuffs outside the body at different temperatures and concluded that the basic factor in digestion is the solvent property of the "gastric juice", a term he introduced. He demonstrated that trituration was not involved other than to make food particles more accessible to this juice. By showing that the solvent action of the gastric fluid can act outside the body, Spallanzani disposed of previously held mechanisms of digestion attributed to mixing aided by heat, putrefaction, trituration, and fermentation, in favor of a chemical theory of solution. However, he failed to recognize that the solvent action of the gastric juice is attributable to its acidity (37).

A new advance came from John Richardson Young (1782-1804) in his MD thesis for the University of Pennsylvania. "An Experimental Inquiry Into the Principles of Nutrition and the Digestive Process" (1803) showed that the solvent principle of gastric juice is an acid and is part of the normal gastric secretion. Experimenting with starving frogs and using litmus paper, Young demonstrated the acidity of gastric fluid, but wrongly concluded that it was phosphoric acid (38-40).

Prout had also favored phosphoric acid as responsible for the acidity of gastric juice, before discovering the true nature of the acid in the stomachs of animals. His report, read before the Royal Society of London on December 11, 1823, was published early in the following year (41). Prout identified free muriatic acid (hydrochloric acid) in the gastric juice of various animals and humans after a meal and suggested that it was derived from the common salt of the blood by the force of galvanism (electricity).

Barely 1 month after Prout's publication, hydrochloric acid was independently identified in gastric juice by a different method by Friedrich Tiedemann (1781-1861) and Leopold Gmelin (1788-1853). They gave Prout credit for the discovery of hydrochloric acid, but they also claimed to have found butyric and acetic acid in the gastric juice. Their investigation was published in Die Verdauung nach Versuchen (2 volumes, 1826-27) (Experiments in Digestion).

Prout's results were confirmed by the classic research of US Army surgeon William Beaumont (1785-1853) on Alexis St. Martin, a 19-year-old French-Canadian fur trapper who developed a gastric fistula that remained after the wound from an accidental gunshot in 1822 had healed. Beaumont studied the appearance and function of the exposed living stomach over several years and provided new information about the nature of the gastric juice and the process of digestion in the stomach. He published his findings in Experiments and Observations on the Gastric Juice and the Physiology of Digestion (1833). Beaumont recognized the acid character of the gastric juice in response to food and alcohol. Its identity as muriatic acid was verified at the University of Virginia and at Yale (42). Old ideas, however, die hard. Writers on gastric physiology continued to deny the presence of hydrochloric acid in gastric juice or mentioned it merely as one of the acids present.

Francois Magendie (1783-1855), a French experimental physiologist, attributed gastric acidity to lactic acid. Because of his reputation, the acid's identity remained an open question for many years, despite Prout's discovery. As late as 1856, Claude Bernard (1813-1878), the prominent French physiologist and former student of Magendie, still accepted his teacher's view.

Investigators considered that the hydrochloric acid was produced secondarily. They believed that the primary acid secreted was lactic acid, which then acted on the sodium chloride present to produce the hydrochloric acid that Prout and others had found. Still others attributed gastric acidity primarily to the presence of acid phosphates in the juice. Only Beaumont had actually handled pure gastric juice, and the material examined was usually mixed with other juices and food residues. Sometimes the juice stood for a time before it was analyzed, long enough for some lactic acid to be produced by fermentation of carbohydrates, especially in gastric contents of low acidity. It was so contrary to physiologic probability that it was difficult for some physiologists to accept the idea that acid as strong as hydrochloric acid, with a pH of 0.9 or less, could be secreted by the living (parietal) cells of the stomach in the mammalian body (9, 43). In 1850, Henry Bence Jones wrote: "This gastric juice, then, is a highly acid fluid secreted by the stomach. ... What acid it is has not yet been determined. Hydrochloric, phosphoric, acetic, lactic, and butyric acids, have each been said to exist in the gastric juice" (44).

All doubt was finally dispelled in 1852 by publication of Gastric Juice and Metabolism. A Physiological-Chemical Investigation by Friedrich Bidder (1810-1894) and Carl Schmidt (1822-1894) of the University of Dorpat. From their quantitative analyses of the gastric juice collected by means of a fistula created in different species of live animals, they demonstrated that the acid of gastric juice is exclusively hydrochloric acid (43).

Final Days

Prout was of middle height and slim figure. The expression of his face combined benevolence with great intelligence, and his bland manner inspired confidence and set the most nervous patient at ease. He always dressed with scrupulous neatness, usually in black, with gaiters or silk stockings. Although Prout had been ailing for some time, his death was relatively unexpected. Sensing his approaching death, he asked that no postmortem examination should be made. Death came from an obscure pulmonary illness, almost certainly an abscess bursting into the lungs (8-10). Prout's discovery of hydrochloric acid in the gastric juice, and that none other was present under normal circumstances--a discovery of fundamental importance in the explanation of the chemistry of digestion--was mentioned either in passing or not at all in his obituaries (9, 10).

Prout was one of those physician-chemists whose investigative work in physiological chemistry contributed to the foundations of modern clinical chemistry. His biography shows how varied were his interests at a time when the boundaries between chemistry and physiology were not clearly separated, defined, or understood. We must study the history of the past--there is nowhere else to look--to understand how we arrived at the present and to prepare for the future. If we ignore history or take it for granted, we would become orphans in time--castaways on a desert island called "the present"--with no idea of where we came from or where we are going.

Received November 14, 2002; accepted January 15, 2003.


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(42.) Rosen G. William Beaumont. In: Gillispie CC, ed. Dictionary of scientific biography, Vol. 1. New York: Charles Scribner's Sons, 1970:542-5.

(43.) Bing FC. Friedrich Bidder (1810-1894) and Carl Schmidt (1822-1894)--a biographical sketch. J Nutr 1973;103:637-48.

(44.) Jones HB. Diagnosis and treatment of stomach and renal diseases. Lancet 1850;1:69-71.

Louis Rosenfeld Address for correspondence: 1417 East 52nd Street, Brooklyn, NY 11234.
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Title Annotation:History
Author:Rosenfeld, Louis
Publication:Clinical Chemistry
Date:Apr 1, 2003
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