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Revista Brasileira de Anestesiologia

Print version ISSN 0034-7094

Rev. Bras. Anestesiol. vol.55 no.2 Campinas Mar./Apr. 2005

http://dx.doi.org/10.1590/S0034-70942005000200010 

>Serendipity in medicine and anesthesiology

MISCELLANEOUS

 

Serendipity in medicine and anesthesiology*

 

A serendipidade en la medicina y en la anestesiologia

 

 

Nilton Bezerra do Vale, TSA, M.D.I; José Delfino, TSA, M.D.II; Lúcio Flávio Bezerra do Vale, M.D.III

IProfessor de Farmacologia e Anestesiologia da UFRN; Anestesiologista da Maternidade Escola Januário Cicco
IIProfessor de Anestesiologista do CCS da UFRN
IIIAnestesiologista da MEJC da UFRN e do Hospital Memorial de Natal

Correspondence

 

 


SUMMARY

BACKGROUND AND OBJECTIVES: This study has evaluated more than a hundred of the most fortunate couplings of a brilliant mind with fortunate luck (serendipity), through the re-reading of most relevant histories on science-related (n = 46) and anesthesiology-related (n = 16) inventions and discoveries.
CONTENTS: This educational article encourages anesthesiologists to appreciate events related to scientific inventions and discoveries, showing that serendipity is possible, provided it is expected. Each discovery or invention includes history, references and scientific or anecdotal explanation. In addition to traditional discoveries, such as wine, gravity, photograph, Velcro, airbag, etc., there are other Medicine-related (microscope, X-rays, vaccine, penicillin, insulin, laser, Paps smear, etc.) and Anesthesiology-related (isometry, gloves, N2O, ether, barbiturates, benzodiazepines, blood patch, etc.) discoveries. Creativity and serendipity may act as cornerstones for clinical and basic research of pioneer inventions for medical and anesthesiologic advances. In fact, topics related to biology, anatomy, physics, chemistry, physiology, pharmacology, astronomy and archeology should be master and … lots of luck.
CONCLUSIONS: Although research and operating room accidents are regrettable, some of them happen and may sometimes lead to spectacular advances, such as heroic treatments and even Nobel Prizes. Open-mindedness is a common trait to those willing to count on grand prize, as American physicist Henry would state (1842): "Seeds of discovery are constantly floating around us, but the onlytake roots in minds well prepared to receive them".

Key words: ANESTHESIA: General, Local; MEDICINE: history; SERENDIPITY


RESUMEN

JUSTIFICATIVA Y OBJETIVOS: En este trabajo fueron examinados más de una centena de los más felices acoplamientos de una mente brillante con la suerte caridosa (serendipidade), a través de la relectura de las más relevantes historias sobre invenciones y hallazgos relacionados a la ciencia (n = 46), a la Medicina (n = 46) y a la Anestesiología (n = 16).
CONTENIDO: Concepto de serendipidade; ejemplos célebres de serendipidade en Ciencia y Tecnología; serendipidade en la pesquisa y práctica médicas; serendipidade en la Anestesiología; serendipidade y creatividad en la pesquisa. A través de la historia del desarrollo médico, la naturaleza probó que el camino más efectivo y más barato en la obtención de drogas, instrumentos y servicios puede ser la suerte casual porque muchos hallazgos son serendípticos. Este artículo educacional alienta el anestesiologista a apreciar los eventos relacionados con invenciones y hallazgos científicos, mostrándole que la serendipidade es posible, desde que sea aguardada. Cada descubierta o invención incluye historia, biografía y explicación científica o anecdótica. Además de los hallazgos tradicionales como pan, vino, gravedad, fotografía, velcro (cinta adhesiva), air-bag, etc., hay otras relacionadas a la Medicina (microscopio, Rayo X, vacuna, penicilina, insulina, láser, esfregadura de Papanicolaou, etc.), y a la Anestesiología, como: isomería, guantes, N2O, éter, barbitúrico, benzodiazepínicos, tampón sanguíneo, entre otros. Creatividad y serendipidade pueden servir de línea maestra para pesquisa clínica y básica de invenciones pioneras para avances médicos y anestesiológicos. Realmente, se deben controlar tópicos relacionados con biología, anatomía, física, química, fisiología, farmacología, astronomía, arqueología y... mucha suerte.
CONCLUSIONES: Aunque accidentes en la pesquisa y en la sala de operación sean lamentables, hay aquéllos que acontecen y, a veces, pueden llevar a avances espectaculares, como tratamientos heroicos y hasta Premios Nobel. Mantener la mente abierta es un trazo común a aquellos que desean contar con la gran suerte, como afirmaba el físico americano Henry (1842): "Las semillas del hallazgo flotan constantemente alrededor nuestro, pero apenas lanzan raíces en las mentes bien preparadas para recibirlas".


 

 

INTRODUCTION

Fear of death, existential vicissitudes and survival requirements were the creative sources of Medicine (the art of curing) and religions (life beyond death) in primitive civilizations. At the light of history, the search for health and life preservation has not always been worth a glorious and altruistic journey, because it would always face social irrationality and selfish attitudes 1-5. Democritus' statement (460 b.C.): "Everything existing in the universe is fruit of chance or need", would result in the popular aphorism: "need is the mother of invention". Following medical and anesthesiologic history lines, one may predict that new technical and scientific advances of this century will continue to greatly overcome major medical inventions and discoveries of the last two millennia.

Fortuitous "accidental chances" will continue to play important role, because they represent 60% of major medical breakthroughs: penicillin, vaccine, anesthesia, DNA, X-rays and microscope, with the granting of three Nobel Prizes 6-13 (Chart I). Increasing influence of physiology, biophysics, biochemistry, pharmacology and monitoring nanotechnology on the fast evolution pace of modern medicine shall go well beyond of what can be imagined today. Undoubtedly, it would be fascinating to anticipate the next steps in managing anesthetic-surgical patients 9-14.

Most important Western Medicine discovery was explaining the closed circuit between heart and vessels through which blood with its nutrients and gases flows. Previous circulation descriptions, such as of the Chinese emperor Huan-Ti (2650 b.C.) and of Roman physician Celsus (50 a.C.), were inconclusive. Harvey's (1628) individual study on circulation has marked the beginning of physiology scientific study through the novel principle of medical experiment. In his De Motu Cordis, the British scientist has obtained anatomic precision dynamization of Vesalius Factory (1543) with promising advances in the physiological study of fundamental aspects of human body and its functions.

Healthy body is a consequence of moving, because life itself is represented by a series of movements in search for homeostasis and rheostasy maintenance of the internal medium, according to principles advocated a posteriori by C. Bernard (1813-1878) and Cannon (1923). As from the 17th century, most major discoveries took place in universities through a scientific method based on Bacon (1561-1626) and Descartes (1596-1650) mechanicist and rationalist concepts, against the empirics of previous speculative methods. The new scientific method started to lead logic and experimental reasoning to elucidate major basic life scientific enigmas 9-19.

Definition of Serendipity

Although scientific progress is commonly considered the result of strict research and consistent multifactorial analysis, one cannot exclude good luck and accidental surprises from discoveries and inventions. More than twenty of major science and medicine inventions, even being worth the Nobel Prize, were consequences of fortuitous chances. So, in developing a research protocol, unexpected facts or consequences of serendipity may be beneficial and even provide new scientific findings.

Many scientific and medical discoveries happened without inventors having the slightest idea of was being discovered. The common link among discoveries, such as X-rays, penicillin, vaccination, stethoscope, anaphylaxis and anesthesia may be luck, chance and bias, not always programmed. According to Pasteur (1848), frequently favored by serendipity, "in the observation field, chances will only favor well prepared minds". American physicist Henry (1842) has expressed similar ideas: "Seeds of discovery are constantly floating around us, but they only take roots in minds well prepared to receive them" 20-25. The Bible has something similar in the sower's parable "and other seed fell into good soil and brought forth grain" (Mc, 4:8) 25. This coincidence or fortuitous chance is implicit in the word serendipity, and medical science history is full of theModelo experimental do Parkinson, pois a injeção provoca lesão dopaminérgica e gabaérgica irreversível Sildenafil (Bloobel,1996). Anti-hipertensivo e anti-anginoso, tendo ereção peniana como efeito colateral Tratamento de disfunção erétilm 14,15,20-24.

Etymologically, English termination - ty has originated from Latin - tatis and medium English - tie, which have evolved to dade in Portuguese: gravity (gravidade), normality (normalidade) reality (realidade), honesty (honestidade), etc., although there are exceptions such as purity (pureza). Serendipity is starting to be part of our daily vocabulary to define fortuitous chances leading to unexpected discoveries, especially in the scientific field.

Most adequate adjective would be serediptic 26,27. As opposed to other words and/or neologisms, the origin of serendipity may be precisely dated: January 28, 1754. British writer and politician Sir Horace Walpole (1717-1797) has used this word for the first time in his letters to define occasional discoveries different from those being looked for. In a letter to his friend H. Mann, he described his luck in finding an old painting of the countess of Tuscan, Bianca Capello: "this discovery is almost like the ones I call serendipity, a very expressive word which, since I have nothing else to tell you, I will explain: once I read a somewhat stupid romance called "The Three Princes of Serendip". While Their Highnesses travel, they were always discovering, by accident or sagacity, things they were not looking for …"

So its origin is Serendip, old Ceylon name (currently Sri-Lanka), a Persian corruption of the Sanskrit Sinhaladvipa, "the island where lions live", for most known names Sinhala or Sinhalese. This is an Eastern story "The Three Princes of Serendip", was published in Venice (1557) by Tramezzino, and talks about the trips of the three sons of King Giaffer with the description of their unexpected discoveries 4,20-24. The Brazilian literature has a folklore character similar to the princes, who is Pedro Malasarte: "he shot what he saw, but killed what he couldn't see"… A more consistent analysis of the "History of the Three Princes of Ceylon" shows that Walpole was betrayed by his memory: serendipity discoveries were not due to chance, because problems and enigmas faced by the princes were solved by sagacious deductions 1-5,20,24.

His intention, in fact, was to create an unfavorable mental state, combining Latin etymology for serene (serena) and stupidity (stupiditas) 20,24,26,27. In the realm of scientific discoveries, serendipity is a fortunate finding for the researcher with his mind prepared to understand the new picture and extract from it consistent deductions, as chemist Pasteur and physicist Henry had already stated 1,4-6. Even logic induction processes should be open and without prejudice, because observation should not be deprived of a certain level of fantasy and abstraction; it should go one step further, enabling deduction ability and allowing the acceptance of the unforeseen not only as a failure but also as a potential problem solution or deviation toward a new discovery. Some authors are even developing special software programs to help the serendiptic research process 5,22.

The linear approach of science development as direct result of rationality is far from reality, since a surprising number of scientific findings are result of fortunate chance: chance and chaos are constantly on our way and may change experimental conditions for better or for worse, since final finding was not directly being looked for 21-24. Beveridge, in his book Seeds of Discovery, distinguishes three types of casual discoveries: 1st - intuition as from overlapping of ideas (inspiration, insight, etc.); 2nd - eureka-type intuition (I found it!); 3rd - serendipity (fortunate accidental discovery) 3,4. There are several opportunities in academic life to experiment serendipity: during routine work, when scientists are looking for results through an experimental hypothesis and a pre-established plan to confirm it.

By practicing serendipity it is possible to find many things outside the initial search if a careful protocol is developed. Some authors have even dreamed of "fortunate chance" the day before the essay (Kekulé's benzene ring in 1865, Loewi's acetylcholine in 1921), while others had the fortuitous insight during a sleepless night (Mestral's Velcro in 1948, Simonetti's enantiomeric mixture in 1999). This modern neologism was born from the fiction imagined in old Ceylon (Serendip) and may now be experienced during a dictionary query (one word is initially looked for and another one is found…); or even when using keywords for Internet queries (Ovid, Medline, favorite sites, etc.).

In fact, some authors already consider the Internet as the major forger of serendipity in modern science world 2,4,6,22. The term has also been extended to name restaurants, shops and travel agencies, among others, where it is expected that customers will make fortunate discoveries, by chance, of very interesting and pleasant things which they were not initially looking for 2,6,24. What is the role of luck or of fortunate chance in serendipity discoveries? In addition to unexpected chance and luck, fortuitous discoveries are different from that being studied by scientific methods, because they require special investigation qualities to "see what others had not seen, and think on what others had not thought" (Szent-Gyorgyi, Nobel Prize 1937).

Serendiptic investigators' qualities are: curiosity, patience, commitment, organization, stubbornness, that is insight ("brain wave") in the right place in the right time, in addition to lots of perspiration and inspiration. It is important, however, to re-explain the role of researchers who have previously dedicated to the same subject with similar objectives. Most spectacular medical discovery - penicillin - is the best known example of serendipity.

If it weren't for the accidental discovery of glass by the Egyptians who cooked clay pottery (6000 b.C.), and if the lenses of van Leeuwenhoek's rudimentary microscope (1675) had not discovered the existence of microbes in a raindrop collected days ago, Fleming (1928) would not have had bacteriological knowledge or interest in observing the growth of Staphylococcus aureus in culture medium; especially when Penicillium mold, which by chance came from the lower hospital floor where mycology was studied, had "contaminated" and prevented the growth of staphylococci.

The previous interest of the Scottish on the bactericidal action of tear lysozyme was also valuable (1922). Chinese, Egyptian and Greek reports bC already refer to the use of moldy bread to treat infected wounds. Fungi-contaminated cultures have generated several observations on bacterial growth among 19th century microbiologists, such as: Penicillium glaucum mold does not inhibit bacterial growth (Roberts, 1874); Anthrax bacillus does not grow in mold-contaminated cultures (Pasteur and Joubert, 1860). Lister (1871), creator of surgical antisepsis, has noted that fungi-contaminated urine samples did not allow for bacterial growth. Duschene's doctoral thesis (1897), describes in animals the antimicrobial efficacy of Penicillium mold.

However, it was only during the London Summer of 1928 that Fleming isolated the fungus inhibiting Staphylococci growth in culture medium and has named it penicillin, although considering unlikely its future systemic use. In fact, if it were not for the efforts of Australian Florey (1898 - 1968) and of Oxford investigators Abraham and Chain (1906 - 1979), penicillin would not have been systemically used for the first time in osteomyelitis (1941), or cultivated in large scale in beer barrels, to be purified, crystallized and universally traded as from the allied war effort to save millions of lives from home or nosocomial infections. Chain, Florey and Fleming have shared the Nobel Prize of 1945 3,10,13,14,20-23.

Notorious Serendipity Examples in Science and Technology

Many accidental technological discoveries are important for our daily lives, even outside the biological field. Discoveries and inventions are not always fruit of super-intelligence or notorious creativity because numerous products, technical procedures and scientific principles were discovered by chance. Sometimes they are fascinating and even anecdotal stories because they reveal the curious and questioning spirit of human minds along time 6-14,16,22. Accidental or not, inventions (bread, wine, microscope, dynamite, Teflon, Velcro, etc.) and discoveries (vaccine, penicillin, X-Rays, plastics, etc.) are human acts impregnated with curiosity, perseverance, stubbornness and luck. Some fortunate chances have already happened before Christ, as bread and wine fermentation.

Bread originated in the old Egyptian civilization: wheat grains were smashed between stones, mixed with water (contaminated with Saccharamyces yeasts) and the dough was dried in the sun until bubbles were seen (CO2 gas from fermented sugar), when it was then warmed between hot stones … recipe that until today still requires time (dough proofing), heat (kneading it at 28 ºC) and love. Grape fermentation by Bortrytis cinerea yeast (peel contamination) to produce wine goes back to 8000 years bC in old Mesopotamia, when some absentminded peasant has forgotten his bunch of grapes 28-30. Finding it some days later, he has eaten the grapes and has become very happy due to alcoholemia! (Exactly what is done today by the blue jay with the pine of Paraná's Araucaria). In the 8th century, Carlos Magno asked for a wine different from the red one that dyed his beard. The monks had produced the white wine (grapes without peels) to grant him. In table II there are the main serendiptic inventions and discoveries in a chronological sequence.

Serendipity in Medical Research and Practice

Systematic research carried out by privileged minds or very stubborn tempers has been successful in achieving its objectives and goals, especially in the academic world. The opening to integrate basic sciences and Medicine was started during the last two centuries of major discoveries and inventions. According to old Chinese reports, witch doctors have discovered that battle wounds caused by darts and arrows were less painful and would more rapidly heal than those caused by other blunt or perforating weapons. Acupuncture was born from this "fortuitous" medical observation by replacing darts by needles to increase "yang" energy during war and peace! Frontiers of natural sciences are no longer well defined and clear in research, and there are always conditions for casual and fortuitous "findings": the search for one result may lead to another, sometimes of greater value 21,22. Serendipity has played a major role in the discovery and development of devices, drugs and treatments; some serendiptic discoveries have even given place to new ideas influencing major scientific investigations of natural phenomena 1,4,20-23,31-48.

Attchment II shows the chronological follow up of serendipity's participation on medical-related discoveries and inventions - devices and pathophysiological processes - as well as the chronological analysis of the evolution of drug and biological therapy throughout times as from serendiptic findings.

Serendipity in Anesthesia

In the history of science and Medicine (Attchment I and II) several and admitted cases of serendipity have radically changed the destiny of humankind. As from urea synthesis (Whöler, 1928), most discovered drugs started to be synthetic, being investigated as from trial and error methods, as opposed to the 19th century when natural drugs prevailed (vegetal, animal and mineral). The discovery of general anesthesia and local analgesia in the 19th century has banned the terror of supposedly implacable suffering and has become a barrier against the torture of irremediable surgical pain.

Attchment III shows the technological advance anesthetic drugs synthesis (analgesics, anesthetics, amnesiacs and muscle relaxants), both nonspecific and those able to selectively interact with central and/or peripheral receptors and neurotransmitters, however without ruling out the participation of serendipity. In addition, there is a re-reading of mechanisms and procedures which are the focus of modern Anesthesiology research, provided they were fruits of serendipity 3,5,21,49-62.

Technical and scientific advances in drugs, monitors and anesthetic procedure-related techniques have slowly increased safety levels by decreasing anesthetic-surgical morbidity and mortality. The first epidural anesthesia performed by Corning (1885) cannot be considered serendiptic, because not even him could understand what he had done; his anatomic conception was wrong and his clinical objectives - treatment and cure of a compulsive masturbator (seminal incontinence) and of a chronic neuropathy - were not reached 60. It is worth stressing that scientific studies in the areas of chronobiology, chronotoxicology and chronopharmacology are showing that rhythm is intrinsic to live matters so that experimental findings related to seasonal and/or circadian variations can no longer be considered casual or serendiptic.

De Virey has shown in 1810 that morphine would promote best analgesic effects at night, because in the morning the constipating action would prevail. Currently, circadian variation of central action liposoluble drugs is well known and an example would be the highest potency of local anesthetic amino-amine during the day, and of etomidate and halothane at night 28,61,62. However, one cannot deny that major scientific (Attachment I), medical (Attachment II) and anesthetic (Attachment III) discoveries may be called serendiptic, in spite of the commitment of the investigator, of accurate sense of observation and of creative skills for the experiment not to go unnoticed by the media.

Serendipity has also influenced therapeutic and tactic option in at least two anesthetic situations, aiming at optimizing results and minimizing complications: post-dural puncture headache treatment and anesthetic preconditioning for anesthetic management of cardiac patients. In this case for cardiac surgeries (1999) the use of halogenate inhalational anesthetics in heart diseases with myocardial ischemia is recommended to improve hemodynamic conditions, when isoflurane had been initially condemned for cardiac patients, especially due to the "stealing" of coronary flow. Urgency in decreasing hospital surgical costs was orienting cardiac surgery toward early discharging patients (fast track).

High opioid doses as single analgesics started to be replaced by short-life inhalational agents, for allowing earlier extubation and ICU discharge, decreased postoperative ischemic episodes and lower hospital costs. Clinical and lab investigations have shown that short ischemic bursts (< 2 h) are protective, that is, they "precondition protecting" against prolonged myocardial ischemic periods 63-65. This mechanism is similar to hormesis and is multifactorial for involving axoplasma and neuronal membrane elements: G protein, PKC, NO, O-- and K+ channel receptors. Halogenate would protect against myocardial ischemia by improving ventricular function and decreasing post-ischemia enzymes release with decreased morbidity and mortality, representing more than just costs reduction or mere hospital savings 34,63,65.

Epidural autologous blood patch is the most effective treatment (93%-97%) for post-dural puncture headache (1% to 70%). Bier, in 1898, has gone through the unpleasant experience of 7 days of post-dural puncture headache, but had already correlated the etiology to liquor hypotension 66. Reviewing his spinal anesthesia records, Gormley (1960) has observed lower incidence of headache in patients in whom blood was seen in the needle during spinal puncture! He then decided to epidurally inject 2 to 3 ml of autologous blood in 7 patients with post-dural puncture headache and has observed total relief in 30 minutes. Only 12 years later, Di Giovanni and Dunbar have returned to the idea and performed more systematic studies (more than 100 cases) with higher volume patches (> 12 ml) with satisfactory results both by closing needle hole with fibrin (inflammatory reaction) and by increasing epidural pressure with less stress on meninges. Currently, prevention consists of fine needles and therapy is divided in stages: 1st - bed rest, fluids and analgesics; 2nd - theophylline, caffeine, ACTH or sumatriptam; 3rd - heroic treatment is epidural autologous blood patch with relief rates of 80% to 90% 24 hours after it is performed, beginning, already in the presence of inflammatory process 34,66-72.

Serendipity and Creativity in Research *

Among philosophical and psychological theories studying creativity, some are descriptive and based on scientists' testimonials stressing the unconscious character of the work, while others emphasize individual motivational and cognitive traits 1-6. Criatividade is also a neologism of the Portuguese language, coming from the English words creativeness and creative. In the Dictionary of Portuguese Language there are several definitions of create: give existence, take from nothing, support, produce, invent, etc. In daily anesthetic practice one may find activities resulting from serendiptic creativity, that is, resulting from something not usual or intentional, but simply casual. Some examples are: conscious sedation with N2O in the medical office, due to its decreased analgesia and mild hallucinogen action (Wells, 1844); induction with thiopental when its precursor, non-sulfurous barbituric acid has no brain effect whatsoever and may even trigger porphyry crisis by inducing D-ALAsynthetase (Bayer,1864; Lundy,1934).

Serendiptic creativity may occur during or outside non-casual creativity process, for example: a posteriori analysis of Aserinsky description on neonates rapid eye movements (REM) by professor Kleitman (1952); it may also happen in different periods, such as Priestley's O2 discovery (1774), which has only been confirmed after its replication by Lavoisier (1777).

On the other hand, intentional or non-serendiptic creativity is far more frequent because it is scheduled with previously defined goals and objectives. Examples: topic cocaine analgesia: there were already some reports on "dormant" tongue by the Incas (1533), von Anrep (1858), Niemann (1860) and Freud (1884). Specially after its dilution in hydrochloric acid performed by Niemann (1860) making it injectable (more stable and soluble in water) with Pravaz or Wood needle (1851) (1853) has given birth to loco-regional anesthesia (Köller, 1884); analgesia and unconsciousness by ether aspiration was the starting point for general Inhalational anesthesia (Morton, 1846). In addition to knowing the work of his chemistry professor on the use of ether for animal anesthesia, there are rumors that a dentist was present during surgeon Long's anesthesias (1842); spinal anesthesia (Bier, 1898) allowing intra-abdominal surgeries in conscious patients was helped by adequate anatomic understanding and the access to large Quincke needle for lumbar puncture (1881) 34-66.

Finally, regardless of serendiptic contribution, experimental success is almost always based on the joint efforts of several investigators and of thinkers preceding them with inspiration and transpiration. If it is easier to observe what is foreseeable and logic, it will always be more difficult to see what goes against all expectations, because a stereotyped view may discredit and render banal the experimental work, even if extremely difficult, creative and provoking. Daring is needed to face laboratory phenomena which "refuse" to respect established theories, provided the possibility of a serendiptic finding is not discarded: today's truth may become tomorrow's "fashion"!

So, updating in the area (basic or applied) should always be investigators' drive, both by periodic literature reviews, and by active participating in courses, seminars or via Internet. Natural phenomena are mechanically linked to each other and are impregnated with historicity, because several discoveries and inventions, serendiptic or not, should largely be credited to those who have previously dedicated themselves to them and whose history should not be forgotten 1,4,5,20,24. Paraphrasing the classic Greek thought: "Gods are more complex in their desires than mortals, the culture of whom is always more ambivalent, a tragedy exhaustively examined in search of a sense for human life".

 

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Correspondence to
Dr. Nilton Bezerra do Vale
Address: Av. Getúlio Vargas, 558/702 Petrópolis
ZIP: 59012-360 City: Natal, Brazil

Submitted for publication May 31, 2004
Accepted for publication October 8, 2004

 

 

* Received from Maternidade Escola Januário Cicco (MEJC) da UFRN

 

 

Attachment I

Attachment II

Attachment III