kinds of information are most useful in selecting applicants who will be successful interns.
REFERENCES
tion and internship performance. JMed Educ 46:670, 1971
5. Kegel-Flom P: Predicting supervisor, peer, and self ratings of intern performance. J Med Educ 50:812, 1975
6. Clemente M, Michener WM: The Deans' letter of recommendation and internship performance. J Med Educ 51:590, 1976
7. Moss TJ, Deland EC, Maloney JV: Selection of med ical students for graduate training: Pass/fail versus grades. N Engl J Med 299:25, 1978
8. Gough HG, Hail B: An attempt to predict graduation
from medical school. J Med Educ 50:940, 1975 9. Gordon MJ, Lincoln A: Family practice resident Se
lection: Value of the interview. J Fam Pract 3:175, 1976
10. Werner ER, Adler R, Robinson R, et al: Attitudes and interpersonal skills during pediatric internship. Pediatrics 63:491, 1979
11. Margolis CZ, Cook CD: Rating pediatric house officer performance. Conn Med 40:539, 1976
12. Rutkow IM, Glasgow AH: How medical students view
the application and interviewing procedure for sur gical residency. J Med Educ 53:505, 1978
BARBARA M. KORSCH, MD EDWENNA R. WERNER, PHD ROBERT ADLER, MD
Children's Hospital of Los Angeles Los Angeles
1. Gardner P, Herbstuman B: Rites of fall: The costs and utility of the internship interview. J Med Educ 53:929,1978
2. Marshall JR, Crowder M, Rice DG: Selection of
psychiatric residents: An overview. J Nerv Ment Dis
155:436,1972
3. Wagoner NE, Gray GT: Report on a survey of pro gram directors regarding selection factors in graduate medical education. J Med Educ, 54:445, 1979 4. Korman M, Stubblefield RL: Medical school evalua
tance. Premature infants have lower serum albumin concentrations and higher serum bilirubin concen trations than do term infants. Prematures also re ceive many drugs and are subject to metabolic stresses which may interfere with the binding of biirubin to albumin.
All of these pieces fit together to form an attrac tive picture: unbound (free) bilirubin is the toxic fraction of the total biirubin pool. Bound biirubin cannot enter cells and is harmless. Put mechanisti cally, the free biirubin theory states that only free biirubin can bind to cells. After binding, toxicity can occur.
I have reviewed the literature to find the experi mental data which prove the free biirubin theory. These were to be summarized here. The sad fact is that there simply are no reported experiments which critically tested the theory.
Of course, some data are consistent with the theory.5 The concept of free bilirubin as the toxic fraction also makes sense. Still, many theories which made eminent sense have turned out to be wrong.
Other mechanisms for biirubin entry are possi ble. As an example, consider the entry of vitamin
B12 into cells.6 Vitamin B12 is transported in the
serum bound tightly to transcobalamin II, just as biirubin is bound tightly to albumin. Yet, it is not the free vitamin which binds to and enters the cell. The entire B12-transcobalamin II complex binds to a cell receptor. The complex undergoes endocytosis, thereby entering the cell. Next, the complex passes into a lysosome. Enzymes within this organelle de Reprint requests to (R.L.L.) Laboratory of Biochemistry, Na
tional Heart, Lung, and Blood Institute, National Institutes of Health, Bldg 3, Room 106, Bethesda, MD 20205.
Bilirubin: Worked Out Years
Ago?
“¿Physiologicalicterus requires no treatment.― L. Emmett Holt, 1897'
Recently, I was talking with an accomplished protein chemist. I mentioned my interest in study ing the binding of biirubin by albumin. Looking very surprised, she exclaimed, “¿Bilirubin!I thought all that was worked out years ago.―This curious impression seems shared by many pediatricians as well. Why?
THE FREE BILIRUBIN HYPOTHESIS
In vitro, biirubin is very toxic to cells and to cellular components such as mitochondria.2 The basis is not established, although several toxic ef fects have been identified. Albumin prevents toxic ity, so long as the molar concentration of albumin exceeds that of biirubin. Similarly, in animals, bil irubin toxicity usually does not occur unless the molar biirubin concentration exceeds that of albu mm.
grade the transcobalamin II. The free vitamin B12 then crosses the lysosomal membrane and becomes available to the cell. So, it is the bound vitamin B12 level in serum which determines the rate of entry of the vitamin into cells. However, through the usual equilibrum equations, there is a relation be tween the concentration of free vitamin B12 and the concentration of bound vitamin B12. Thus, there is a correlation between the concentration of free vitamin and total transport into cells. Obviously, simple correlations mislead about underlying mech anisms.
This and other transport mechanisms could op erate in the transport of bilirubin into cells. Do not assume that free bilirubin is involved—even if it makes sense.
THE BLOOD-BRAIN BARRIER
The role of the blood-brain barrier in bilirubin toxicity remains unknown. The free bilirubin hy pothesis assumes that albumin-bound bilirubin is excluded from the central nervous system. Free bilirubin is assumed to have ready access to the brain by virtue of the lipid solubility of bilirubin. Unfortunately, nothing is sacred these days. The idea that bilirubin is lipophilic and apolar is wrong. Brodersen7 has marshalled data which demonstrate that bilirubin is not a lipid-soluble molecule. Bili rubin is a polar, charged molecule which should be excluded from the brain by an intact blood-brain barrier.
Earlier notions of an immature blood-brain bar rier in newborns seem poorly grounded.8 The pre mature or term newborn brain does take up many molecules faster than the adult brain. This does not imply an immature barrier; it can result simply from differences in metabolism of the young, grow ing brain.
The effect of reversible opening of the blood brain barrier is now amenable to experimental in quiry. This could prove important in understanding kernicterus. Serum albumin readily enters the brain during reversible opening of the barrier caused by hyperosmolar ns9'° Although only seven re gions were examined, the regional pattern of uptake was consistent with the distribution seen in kernic terus. The highest uptake of albumin occurred in the caudate nucleus. A recent paper reported the exciting finding that the brain takes up exogenously administered enzymes when the barrier is reversibly opened.' ‘¿The enzymes appear in the interior of neurons, rather than in glia. Would kernicterus result if the blood-brain barrier were opened in the presence of hyperbiirubinemia?
Anoxic-ischemic stress can open the blood-brain barrier, sometimes reversibly.8 This relatively re
cent finding illuminates older work in which ani mats were made hyperbiirubinemic. In those stud ies kernicterus could not be produced unless the animals were also asphyxiated.'2―3
The time of the barrier opening following anoxia ischemia varies with the length of the insult. In one model, cerebral blood flow was blocked in gerbils.'4 If flow was restored after 30 minutes, the barrier
opened some 20 hours later, but only in half of the animals. If flow was restored after six hours occlu sion, then the barrier opened in all animals within one hour. These results obviously bear on the din ical observation that kernicterus is more likely to occur in infants asphyxiated at birth, but with onset of symptoms several days after asphyxia.
MEASUREMENT OF FREE BILIRUBIN
Lee and Gartner'5 provided a recent, valuable review of most methods which purport to measure
free biirubin. I do not want to duplicate their
contribution and will simply discuss three general problems.
First, measurement of free biirubin has proven very difficult. The basic problem lies in the ex tremely tight binding of biirubin to albumin. The affinity constant is on the order of 108 M'. This means that bilirubin binds 10,000 to 100,000 times more tightly than do most drugs. The usual physical methods for separating the free from bound species just do not work with such tight binding.
Consider the use of ultrafiltration. Special ultra filters are available which pass small molecules, while retaining larger ones such as albumin. Small molecules bound to proteins will not pass the filter, while the unbound molecules flow through. Mea surement of the ultrafiltrate gives the concentration of the free species.
This technique works well in measuring the un bound concentration of substances which do not bind very tightly. For example, the method can determine the concentration of unbound calcium.'6 The best filters are about 98% to 99% efficient; only about 1% of the protein (and hence, protein-bound species) leaks through. Since about 50% of serum calcium is free, the 1% leakage causes no problem. But over 99.999% of bilirubin is albumin-bound. A leakage of even 0.1% albumin will contaminate the ultrafiltrate with 100 times the true free biirubin.
because Sephadex itself binds bilirubin.'8 Some in vestigators, being aware of this problem, suggest that the amount of bilirubin bound by the Sephadex column might still provide some assessment of the risk of impending kernicterus. However, no studies fully reported have critically tested the value of Sephadex monitoring. The one followup study available has only been published as an abstract.'9 That study found no correlation between Sephadex bound bilirubin and outcome at one year of age.
Third, there are methods available which do ap pear to measure free bilirubin—at least in model systems constructed with pure bilirubin and albu mm. The peroxidase method is the best developed and most promising at present.2° Very simply, horseradish peroxidase can react with free bilirubin, but not with bound bilirubin. The rate of the reac tion is directly proportional to the concentration of free bilirubin. The method is simple, and a useful automation has now been described.2'
Problems arise in moving from model systems to serum. The major complication introduced by working with serum is that of effectors. Effectors are simply inhibitors or stimulators of the peroxi dase. Although I shall continue to use the peroxi dase example, similar problems occur with all other methods which measure free bilirubin in model systems.
To determine the free bilirubin concentration in serum, one measures the rate of the peroxidas@ reaction and compares it to the rate from a standard curve. However, the standard is essentially con structed by measuring the rate of reaction of per oxidase with pure bilirubin in the absence of serum. Peroxidase, being an enzyme, can be affected by the milieu of the serum. Consequently, the rate of re action in serum may be different from that in the standard, even though the free bilirubin concentra tion is the same in both serum and standard.
Serum contains myriad components which could act as effectors. If these vary from patient to patient or with time, the peroxidase method could give erroneous results. Some components are already known to be substrates for peroxidase.22 These will likely act as competitive inhibitors. For example, vitamin C is a known peroxidase substrate. Vitamin C in serum could introduce significant errors in the peroxidase results, giving falsely low values for the
free bilirubin concentration.
Conversely, other compounds stimulate the activ ity of peroxidase.22 This could result in falsely ele vated values of serum free biirubin. Substances with an aromatic ring have long been known to stimulate peroxidase. Szent-György23 included his observations on this phenomenon in his paper re porting the isolation ofvitamin C. In short, effectors may variably alter the activity of peroxidase, lead
ing to errors in the measurement of free bilirubin in serum. Although it may be possible to correct for effector artifacts, the problem has not yet been addressed in the literature.
CLINICAL USE OF FREE BILIRUBIN
MEASUREMENTS
I noted above that there is as yet no proof for the free biirubin theory. Also, there are difficulties in measuring free bilirubin concentrations in serum. Are the available tests useful in managing jaundiced newborns? Several participants in the Conference on Neonatal Bilirubin Determination recently pub lished their opinion of tests which have been used to date.24 (Most of the tests they considered do not measure free bilirubin. What they measure is a matter of conjecture.)
While recognizing the need for more clinical stud ies, those authors suggested that available tests may be helpful in monitoring jaundiced patients. That opinion seems to be based on optimism about the future because there are no convincing studies demonstrating the value of such measurements. Surprisingly, I could not find even a single followup study of unselected patients who have had free biirubin determinations. There were also no studies which tested the value of these measurements in deciding when to institute treatment for hyperbili rubinemia.
Such studies must be performed before any test can be recommended for use in making therapeutic decisions. Careful planning of the studies could avoid expected pitfalls.25 It will not be enough to show that a correlation exists between free bilirubin and the risk of kernicterus. As already mentioned, there has to be some correlation. This is because the free bilirubin concentration is correlated with the total bilirubin concentration, and total bilirubin concentration is a known predictor of kernicterus. We must have clinical studies which prove that the free biirubin concentration is a better predictor of risk than the readily available total biirubin con centration or the biirubin/albumin ratio.
BILIRUBIN TOXICITY
ward gaze, and dental dysplasia.2@ The evidence is strong, but not conclusive, that bilirubin is the toxic substance causing neural damage. However, it may be that bilirubin is only a colorful marker of some other damaging event. For example, assume that damage to the blood-brain barrier is the primary mechanism. Upon opening of the barrier, bilirubin and many other compounds will gain access to areas of the brain from which they are normally excluded.
Kernicterus in term infants has almost disap peared in most developed countries. The ability to treat hyperbilirubinemia and erythroblastosis par tially accounts for this success.27 However, the dra matic decrease in incidence of Rh sensitization re moved most of the babies at risk.27'28 Many physi cians assume this decreased incidence was due to an advance in preventive medicine—the use of anti Rh globulin (RhoGAM). In fact, much of the de crease in serious Rh sensitization can be explained by the reduction in family size which occurred in the last 20 years.27'29 Clinically severe sensitization is seen in later pregnancies, especially after the third. With few women now having that many pregnancies, there will not be many severely sensi tized babies born.
Kernicterus in premature infants is usually not related to isoimmunization, a point made 30 years ago. Kernicterus may be clinically silent in prema tures, with the diagnosis being made only at au topsy. Further, kernicterus has been reported at low serum biirubin concentrations in prema tures.'°32 These case reports stimulated the current practice of treating prematures at relatively low concentrations of serum biirubin. Some pediatri cians routinely perform exchange transfusions when the serum biirubin (in mffligrams per 100 ml) ex ceeds 1% of the infant's weight (in grams). So, an 800 gm baby would be exchanged when his serum biirubin reached 8 mg/100 ml.
In fact, there are no studies which establish risk levels in the smaller prematures. These are urgently needed and ought to be performed. The current incidence of kernicterus in prematures is unknown. As best I can learn, it is variable but uncommon in the United States and Canada. From this observa tion one might argue that our current aggressive treatment works. If so, a study in which babies might be treated at higher biirubin levels would be unethical. But how many babies die or suffer serious sequelae due to unnecessary treatment? No one will know until a randomized, controlled trial is done.
I have been talking about the smaller premature. What of the larger premature, say 1,500 to 2,500 gm, or 32 to 38 weeks gestation? Again, there are no recent studies to guide decision making. How ever, there are studies from the pre-intensive care era.@'@ These found that risk of kernicterus was
low if exchange transfusion be performed at biliru bin levels of 20 mg/100 mi—just as in term babies. These carefully executed studies are generally ig nored these days, presumably because of the ret rospective case reports I mentioned above.8@'2
Those case reports described kernicterus in pre matures with peak serum bilirubins below 20 mgI 100 ml. I think it possible that some of those babies were exposed to a potentiating agent or event that went unrecognized. By potentiating agent, I mean a chemical with an effect like sulfisoxazole in in creasing the risk of kernicterus.― Such a potentiat ing agent or event could easily have been missed. Sulfisoxazole was widely used in prematures before Silverman discovered its devastating effect. He was able to identify this effect because he was carrying out a well-designed clinical trial.
Moreover, we do not know whether these unusual cases of kernicterus at low serum bilirubin can be prevented by more aggressive treatment of hyper biirubinemia. Exchange transfusions performed at 10 mg/100 ml may be no more efficacious than those performed at 15 or 20 mg/100 ml. This might well be the case if kernicterus does result from opening of the blood-barrier with influx of albumin bound biirubin.
OTHER TOXIC EFFECTS
Kernicterus is the only syndrome which has been proven to be preventable by treatment of hyperbi lirubinemia. Of course, for many years hyperbiliru binemia has been suggested as a cause of milder problems.26 Hyperbilirubinemia has been indicted as causing impairment of intelligence (IQ), dyslexia and other learning disabilities, hyperactivity, and poor coordination.
Many pediatricians tell me that they aggressively treat hyperbilirubinemia in prematures in order to prevent these “¿softersequelae.― Yet there is no evidence that biirubin actually causes any of the problems listed. Moreover, there is no evidence that treatment of babies at lower levels of serum biliru bin leads to a better outcome.
The reports of the Collaborative Study on Cere brat Palsy are often cited in support of aggressive treatment of jaundice in prematures.'7'@ This mas sive perinatal study gathered neurologic and devel opmental information on 25,000 babies born in the early 1960s. Outcome at eight and 12 months was determined and correlated with peak serum biliru bin levels. Impaired motor performance on the Bay ley examination was associated with elevated serum biirubin (in the range of 10 to 14 mg/100 ml or higher).
There are two key points to consider. First, the
erate hyperbilirubinemia and poorer motor scores
on the Bayley examination. No causation could be or was assumed. Babies with higher biirubin levels were probably beset with more problems than ba bies with lower bilirubin levels (eg, respiratory dis tress, hypoglycemia, hypothermia, intracranial hemorrhage, and hyperviscosity). While hyperbili rubinemia may be a marker for higher risk infants, the poorer outcome may not be due to bilirubin toxicity.
Second, it remains to be proven that early, ag gressive treatment with phototherapy or exchange transfusion actually improves outcome.
These same criticisms apply to other unproven hypotheses in the field, especially those concerning the toxicity of free bilirubin.24―9
CONCLUSIONS
1. The free bilirubin theory proposes that un bound bilirubin binds to and enters cells. The the ory is simple, reasonable, and attractive.
2. To date, there is no evidence to support the free biirubin theory over other possible mecha nisms.
3. The measurement of free bilirubin is now tech nically possible for mixtures of purified biirubin and albumin. Measurement in serum is promising, but proven methods still elude current capabilities. 4. At present, there is no justification for the use of free bilirubin tests in the management of jaun dice. This evaluation holds for related tests, regard less of aliases: reserve binding capacity, biirubin binding capacity, albumin saturation, loosely bound biirubin, gel bound biirubin, and binding affinity. 5. For smaller prematures, the concentration of total bilirubin at which the risk of kernicterus ex ceeds the risk of treatment is unknown. There is no scientific basis to guide the clinician in deciding when to institute treatment of jaundice in these babies.
6. Hyperbiirubinemia can lead to kernicterus. Whether it causes other, milder forms of neurologic and developmental damage is unknown. At present, there is no basis for treating jaundice with the hope of preventing such damage.
RODNEY L. LEVINE
Laboratory of Biochemistry
National Heart, Lung, and Blood Institute National Institutes of Health
Bldg 3, Room 106 Bethesda, MD 20205
REFERENCES
1. Holt LE: The Diseases oflnfancy and Childhood, ed 1. New York, D Appleton, 1897,p 78
2. Cowger ML: Biirubin encephalopathy, in Gaull GE
(ed): Biology ofBrain Dysfunction, vol 2. New York, Plenum Press, 1973, pp 265—293
3. Lathe GH: Exchange transfusion as a means of re moving biirubin in haemolytic disease of the new born. Br Med J 1:192, 1955
4. Odell GB: The distribution and toxicity of bilirubin.
Pediatrics 46:16, 1970
5. Diamond, I, Schmid R: Experimental bilirubin en
cephalopathy. The mode of entry of biirubin-'4C into the central nervous system. J Clin Invest 45:678, 1966 6. Rosenberg LE: Disorders of proprionate, methyl
malonate, and cobalamin metabolism, in Stanbury JB, Wyngaarden JB, Fredrickson DS (eds): The Met abolic Basis of Inherited Disease, ed 4. New York, McGraw-Hill Book Co, 1978, pp 411-429
7. Brodersen R: Biirubin: Solubiity and interaction with albumin and phospholipid. J Biol Chem 254: 2364, 1979
8. Rapoport SI: Blood-Brain Barrier in Physiology and Medicine. New York, Raven Press, 1976
9. Chiueh CC, Sun CL, Kopin IJ, et al: Entry of [:IH] norepinephrine, [125J}albumin and Evans Blue from blood into brain following unilateral osmotic opening of the blood-brain barrier. Brain Res 145:291, 1978
10. Rapoport SI, Hon M, Klatzo I: Reversible osmotic
opening of the blood-brain barrier. Science 173:1026,
1971
11. Barranger JA, Rapoport SI, Fredericks WR, et al: Modification of the blood-brain barrier: Increased concentration and fate of enzymes entering the brain. Proc Natl Acad Sci USA 76:481, 1979
12. Lucey JF, Hibbard E, Behrman RE, et at: Kernicterus in asphyxiated newborn Rhesus monkeys. Exp Neu rol 9:43, 1964
13. Chen H-C, Lien I-N, Lu T-C: Kernicterus in newborn rabbits. Am J Pathol 46:331, 1965
14. Ito U, Go KG, Walker JT Jr, et al: Experimental cerebral ischemia in Mongolian gerbils. III. Behavior of the blood-brain barrier. Acta Neuropathol (Berl) 34:1, 1976
15. Lee K-S, Gartner LM: Biirubin binding by plasma proteins: A critical evaluation of methods and clinical implications. Rev Perinat Med 2:319, 1978
16. Nordin BEC (ed): Calcium, Phosphate and Magne sium Metabolism. Edinburgh, Churchill Livingstone,
1976, pp 173—174,537—538
17. Jirsová V, Jirsa M, Henngová A, et al: The use and possible diagnostic significance of Sephadex gel filtra tion of serum from icteric newborn. Biol Neonat 11: 204, 1967
18. Kaufmann NA, Kapitulnik J, Blondheim SH: The adsorption of biirubin by Sephadex and its relation ship to the criteria for exchange transfusion. Pediat rics 44:543, 1969
19. Wirth FH, Goldberg KE, Lubchenco LO: The neu rologic outcome of infants evaluated for unbound biirubin. Pediatr Res 9:385, 1975
20. Jacobsen J, Wennberg RP: Determination of un
bound biirubin in the serum of newborns. Cliii Chem
20:783,1974
21. Wennberg RP, Rasmussen LF, Ahlfors CE, et al: Mechanized determination of the apparent unbound unconjugated biirubin concentration in serum. Clin Chem 25:1444, 1979
22. SaundersBC, Holmes-SiedleAG, Stark BP: Peroxi
dase. London, Butterworths, 1964
peroxidase systems and the chemistry of the adrenal cortex. Description of a new carbohydrate derivative. Biochem J22:1387, 1928
24. Cashore WJ, Gartner LM, Oh W, et al: Clinical ap
plication of neonatal bilirubin-binding determina tions: Current status. J Pediatr 93:827, 1978
25. Ransohoff DF, Feinstein AR: Problems of spectrum
and bias in evaluating the efficacy of diagnostic tests. N Engi J Med 299:926, 1978
26. Perlstein MA: The late clinical syndrome of postic teric encephalopathy. Pediatr Clin North Am 7:665, 1960
27. Knox EG: Control of haemolytic disease of the new born. Br J Pret' Soc Med 30:163, 1976
28. Center for Disease Control: Rh Hemolytic Disease Surveillance, 1974. Atlanta, DHEW Publication
(CDC) 76-8310, 1976
29. National Center for Health Statistics: Final Natality Statistics, 1977. Hyattsville, MD, DHEW Publication (PHS) 79-1120, vol 27, no 11, supplement, Feb 5, 1979 30. Stern L, Denton RL: Kernicterus in small premature
infants. Pediatrics 35:483, 1965
31. Gartner LM, Snyder RN, Chabon RS, et al: Kernic terus: High incidence in premature infants with low serum bilirubin concentrations. Pediatrics 45:906,
1970
32. Ackerman BD, Dyer GY, Leydorf MM: Hyperbiliru binemia and kernicterus in small premature infants. Pediatrics 45:918, 1970
33. Hugh-Jones K, Slack J, Simpson K, et a!: Clinical course of hyperbiirubinemia in premature infants. N
Engi J Med 263:1223,1960
34. Shiler JG, Silverman WA: “¿Uncomplicated―hyper biirubinemia of prematurity. Am J Dis Child 101:
587,1961
35. Wishingrad L, Cornblath M, Takakuwa T, et al: Studies of nonhemolytic hyperbilirubinemia in pre mature infants. I. Prospective randomized selection for exchange transfusion with observations on the levels of serum biirubin with and without exchange transfusion and neurologic evaluations one year after birth. Pediatrics 36:162, 1965
36. Silverman WA, Andersen DH, Blanc WA, et al: A difference in mortality rate and incidence of kernic terus among premature infants allotted to two pro phylactic antibacterial regiments. Pediatrics 18:614, 1956
37. Boggs TR Jr, Hardy JB, Frazier TM: Correlation of neonatal serum total biirubin concentrations and developmental status at age eight months. J Pediatr 71:553, 1967
38. Scheidt PC, Mellits ED, Hardy JB, et al: Toxicity to biirubin in neonates: Infant development during first year in relation to maximal neonatal serum biirubin concentration. J Pediatr 91:292, 1977
39. Brodersen R: Prevention of kernicterus, based on recent progress in biirubin chemistry. Acta Paediatr
Scand 66:625,1977
PICKWICKIAN SYNDROME
A classic description of the association of the signs and symptoms of the PICKWICKIAN SYNDROME was written by Charles Dickens. The author refers to “¿afat and red-faced boy in a state of somnolency.― This boy was subsequently addressed as YOUNG DROPSY, YOUNG OPIUM-EATER AND YOUNG BOA CONSTRICTOR—no doubt in reference to his obesity, his somnolence and his excessive appetite.
A characteristic of these patients is an extraordinary degree of somnolence in which sleep may overcome the patient while he is sitting up or even while he is engaged in conversation or other muscular activity.
Submitted by M. Yirka
1979;64;380
Pediatrics
Rodney L. Levine
Bilirubin: Worked Out Years Ago?
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Bilirubin: Worked Out Years Ago?
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