Herman Award Lecture, 1 995: Infection-induced

malnutrition-from cholera to cytokines12

William R Beisel

ABSTRACT Infection-induced malnutrition, the most com- elderly people, and in seriously ill patients, infection-induced
mon form of cytokine-induced malnutrition, results from the ad- malnutrition can become life-threatening.
tions of proinflammatory cytokines, ie, tumor necrosis factor The title of this lecture reflects the progression of my studies
(TNF) and interleukins 1, 6, and 8 (IL-i, IL-6, and IL-8). During of infection-induced malnutrition over four decades, as shown
acute generalized infections, these cytokines initiate the acute- in Figure 1. These studies began when I was Chief of the
phase reaction. This reaction is quite stereotyped, and includes Department of Metabolism and the Metabolic Research Ward
fever, malaise, myalgia, headaches, cellular hypermetabolism, and at Walter Reed Army Institute of Research. In 1959, I was

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multiple endocrine and enzyme responses. In addition, there is asked to lead a small Army team to join Navy and Thailand
heightened catabolism of muscle proteins and many amino acids; investigators in studying the metabolic and physiologic aspects
flux of free amino acids into the liver; hepatic synthesis of acute- of cholera during an outbreak in Bangkok. Also, while at
phase plasma proteins; sequestration of iron and zinc; gluconeo- Walter Reed, Bob Herman was one of my resident physicians.
genesis; insulin resistance; impaired cellular uptake of fatty acids Thats where we first began to collaborate on bench research
from plasma triglycerides; sizable losses of body nitrogen, potas- projects. Our first collaborative paper was published in 1962 (2).
sium, magnesium, phosphate, and zinc; retention of body salt and After completing the cholera studies, I was transferred to the
water; heightened metabolic degradation and/or loss of vitamins; Army Medical Laboratory at Fort Detrick, MD, subsequently
and an activation of the immune system. The pathogenesis of named the US Army Medical Research Institute for Infectious
cytokine-induced malnutrition is thus vastly different from the Diseases. My mission there was to investigate the metabolic
malnutrition caused by uncomplicated starvation. Cytokine-in- aspects of nondiarrheal infections. These studies continued for
duced malnutrition can have a devastating effect on the immune >20 y. Bob Herman and his wife Yaye would visit me there so
system and its functions. Although proinflammatory cytokines are that we could do bench research studies together. Together,
found in mucosal fluids, where they contribute to the pathogenesis they generated the major data for our last collaborative paper
of inflammatory bowel diseases, it is not known whether cytokines on vitamin metabolism and infection (3). For the past decade,
play a role in toxigenic, secretory diarrheas such as cholera, which I have been teaching about infection-induced malnutrition and
cause huge losses of body water, electrolytes, and bicarbonate while nutritional immunology.
exhibiting no systemic manifestations of an acute-phase reaction. Several key milestones along the way included conferences
A,n J Clin Nutr 1995;62:813-819 and workshops sponsored by the National Academy of Sci-
ences and the American Medical Association, meetings that I
KEY WORDS Infection, cytokines, interleukins, malnutri- chaired or helped to organize. Each meeting led to important
tion, nitrogen, protein, lipids, amino acids, endocrines, glucose, early publications (4-6). These included the first book on
trace elements, electrolytes, vitamins, acute-phase reaction, malnutrition and the immune response (4), edited by Suskind;
cholera, diarrheas, immune system, nutritionally acquired im- the first comprehensive symposium on infection-induced mal-
munodeficiency syndrome, NAIDS nutrition (5), which occupied two full issues when published in
1977 by The American Journal of Clinical Nutrition (AJCN);
and the first comprehensive monograph on single nutrients and
INTRODUCTION immunity (6), also published as a 1982 supplement to AJCN.
Most recently, in 1992, the Journal ofNutritional Immunology
This Herman Award is very special to me, and I sincerely
was begun.
appreciate the honor that it brings. I cherish this award deeply
because Bob Herman was one of my closest friends and col-
leagues for many years. His untimely death created a great loss CHOLERA STUDIES
for all of us who knew him (1), and for this Society as well.
In the Bangkok studies (7-9), our group completely rede-
This Bob Herman Lecture now allows me to discuss a long-
fined the existing textbook concepts about the pathogenesis and
term interest, that is, infection-induced malnutrition, or, in
more modern terminology, cytokine-induced malnutrition. 1 From the Department of Molecular Microbiology and Immunology,
Acute febrile infections induce important losses of body The Johns Hopkins School of Hygiene and Public Health, Baltimore.
nutrients. These losses can become quite large during severe, 2 Address reprint requests to WR Beisel, 8210 Ridgelea Court,

prolonged, or frequent infections. In infants and children, in Frederick, MD 21702-2938.

Am J Clin Nuir 1995:62:813-9. Printed in USA. C 1995 American Society for Clinical Nutrition 813
814 BEISEL

FROM CHOLERA TO CYTOKINES METABOLIC BALANCE STUDIES

IPersonal Contributions]

1955 Because of the early successes with cholera, I was given the
WRA IR
opportunity to initiate comprehensive studies of metabolic,
endocrinologic, physiologic, and nutritional effects of nondi-
CHOLERA STUDIES
1960 arrheal infections in research volunteers, as well as in labora-
-- S
ARMY MEDICAL INFECTIOUS DISEASE
tory animals. Initial data were obtained by using metabolic
UNIT (Fort STUDIES INITIATED balance techniques (1 1) and by measuring adrenocortical hor-
Detrick, MD)
1965 mones (12). According to the prevailing concepts in the early
1960s, responses to stress were largely initiated and controlled
USAMR I ID by the adrenal cortex.
1970 For the balance studies (11), volunteers were hospitalized 2
LEM (IL-i) & CYTOKINE
-- 5*
wk before their purposeful exposure to an infectious microor-
EFFECTS D I SCOVERED
ganism. They were begun on a constant liquid diet that met all
NAS WORKSHOP on
1975 NUTRITION & IMMUNITY nutritional needs. Specimen collections were begun 9 d before
exposure and were continued throughout the full course of
NAS CONFERENCE on
INFECTION & NUTRITION illness.
Clinical illness was accompanied by anorexia and dimin-
1980 ished food intake. Stool nitrogen losses did not increase, but
AMA WORKSHOP on SINGLE urinary nitrogen excretion increased slightly. This combination

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NUTRIENTS & IMMUNITY
of events produced sharply defined losses of body nitrogen
THE JOHNS 1985 HOPKINS COURSES on soon after clinical illness began. Daily losses of nitrogen gen-
HOPKINS SCHOOL Nutrition, Irvinunity,
OF HYGIENE & and Infection crated a large cumulative body deficit. When the patients were
PUBLIC HEALTH
clinically ready for discharge, they were not yet beginning to
reconstitute their large deficiency of body nitrogen (1 1).
1990
Balance measurements of other major intracellular dc-
JOURNAL OF NUTRITIONAL
IMMUNOLOGY Initiated
ments-potassium, magnesium, and phosphate-followed pat-
terns of loss quite similar to those of body nitrogen (1 1). Zinc
1995
and sulfur losses also developed. On the other hand, sodium,
chloride, and water were retained by the body during the acute
S First, & 5* Last Paoers with Robert H. Herman illness, and then lost by diuresis during convalescence (1 1).
Paired-feeding studies in noninfected volunteers demon-
FIGURE 1. Temporal representation of the authors studies of infec-
strated only small transient losses of body nitrogen (1 1). These
tion-induced malnutrition. WRAIR, Walter Reed Army Institute of Re-
losses were rapidly regained. Other control studies showed that
search; USAMRIID, US Army Medical Research Institute for Infectious
Diseases; IL-i, interleukin 1; NAS, National Academy of Sciences. the hypermetabolism of artificially induced fevers caused sim-
ilar large losses of body nitrogen and other elements (13). In
contrast, nitrogen balance was not altered by the antibiotics
used in therapy, or by hydrocortisone, when given in daily
amounts that matched adrenal gland production during infec-
therapy of cholera. We found that the intestinal mucosa did not
tion (11).
slough off during cholera (7), as previously believed. Rather,
Once the metabolic balance studies were nicely underway, a
the intestinal mucosa remained intact. Instead, toxin produced
continuing series of brilliant young physicians and newly grad-
by the Cholera vibrio cells caused specific absorptive dysfunc-
uated PhDs began to be assigned to my laboratories for their
tions in mucosal cells. These toxic effects produced diarrheal
tour of Army service. They contributed much to subsequent
losses of hugh quantities of water, sodium, potassium, and
endocrine, biochemical, and metabolic studies. Morton I
bicarbonate (7, 9). Cholera stools were highly alkaline, and the
Rapoport joined me in research on adrenal function and tryp-
enormous losses of body bicarbonate initiated a severe sys-
tophan metabolism (14-18). George E Shambaugh, III, inves-
temic acidosis (9).
tigated changes in thyroid function, glucose tolerance, insulin
Proper fluid and electrolyte-replacement therapy, with cor-
secretion, and tyrosine metabolism (19-23). George Lust per-
rection of the acidosis, proved life saving. These early studies formed biochemical studies documenting host enzyme re-
in Bangkok brought cholera research into the modern era, and sponses (17, 24, 25).
helped set the stage for the subsequent purification and char- Ralph D Feigen explored changes in plasma amino acids and
acterization of the cholera toxin, discovery that cholera toxin the antidiuretic hormone (26-28); Albert S Kleiner inquired
stimulated
cyclic AMP
adenylate
(adenosine-3
cyclase to cause
:5 -cyclic
a marked
monophosphate)
increase
in gut
of into changes in plasma proteins (26, 29, 30). Kenneth A Woe-
ber measured growth hormone responses (3 1). Robert H Feiser
mucosal cells, discovery that intestinal absorption of glucose (32-35), and later, Robert L Kaufmann (36, 37), investigated
during cholera facilitated the absorption of salt and water, and changes in lipid metabolism, whereas Elliot J Rayfield (38-41),
formulation of the World Health Organization packets of sugar David I George (38-41), and Randall I Curnow (38-40)
and electrolytes currently used for oral rehydration therapy in performed additional studies on glucose metabolism and its
children with severe secretory diarrheas (10). related hormones.
 INFECTION-INDUCED MALNUTRITION 815

ENDOCRINOLOGIC STUDIES insulin responses, giving evidence for the sudden development
of cellular insulin resistance (19, 38-40). However, the high
Adrenal gland plasma glucagon values did decline appropriately, when the
When studied prospectively, we found that plasma cortisol glucose was given (38-40).
lost its usual circadian periodicity during the acute phase of
Evaluation of endocrine responses during infection
infectious diseases. Instead, plasma cortisol maintained its nor-
mally high morning concentrations throughout the entire day In evaluating our early endocrinologic findings during acute
and night (12). Increases in urinary glucocorticoids and ketos- infectious illnesses, two important general conclusions could
teroids were actually quite small. These increases quickly re- be drawn. First, endocrinologic responses to acute infection
verted to normal when patients began to recover (12). Thus, the simply could not explain the numerous metabolic and biochem-
adrenal cortex clearly did not control the entirety of the hosts ical events that characterized the totality of the bodys complex
metabolic response to the stress of infectious diseases. Other response to acute infectious disease. And second, the multiple
investigators showed that adrenocorticoid excretion was sub- endocrine responses seen during acute infection were similar
normal during chronic infections (14). In contrast, plasma to, and actually typified, the endocrine responses seen during
cortisol values could become very high during life-threatening other forms of stress.
illnesses. Such high values were caused by a failure of the liver
to convert plasma cortisol to its water-soluble metabolites. OTHER METABOLIC RESPONSES TO ACUTE
Unlike the glucocorticoids, aldosterone secretion patterns mim- INFECTION
icked the febrile response pattern, and accounted for the acute
renal retention of body sodium and chloride (12). As shown by Our combined metabolic and physiologic studies generated

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others, adrenomedullary catecholamine values in plasma be- much fundamental information on a wide range of host re-
come markedly elevated during episodes of septic shock (41). sponses to infection. Importantly, Robert W Wannamacher, Jr,
(44-5 1) became the senior biochemist of our group and worked
Thyroid gland with Robert S Pekarek (45, 48, 50-54) and Michael C Powanda
(47, 48, 50, 55, 56) on a wide variety of studies concerned with
Shambaugh and I (20, 21) found a rapid decline of plasma
changes in trace element, amino acid, and protein metabolism,
protein-bound iodine, and a decreased binding of thyroxine to
plasma proteins during acute infection. In laboratory rats, these and the mediators that brought about these changes. Later,
Philip Sobocinski and his team discovered the rapid, infection-
changes were accompanied by a marked slow down of hor-
induced synthesis of the hepatic metallothionein, which caused
mone production by the thyroid gland. This infection-induced
sequestration of zinc (57). Outside collaborators included
evidence of hypothyroidism appeared to be caused by a de-
David F Clyde, Herbert L DuPont, and Richard B Hornick of
creased thyroidal responsiveness to thyroid stimulating hor-
the University of Maryland (29, 51); Robert L Squibb at
mone; (TSH) as well as by a diminished responsiveness of the
Rutgers (58), Buford L Nichols and his group at Baylor (59);
anterior pituitary gland to declining concentrations of free
and Robert S Lees (33) of the National Institutes of Health
thyroxine in plasma. Thyroid physiology returned to normal
(NIH). These findings led to the development of new concepts
during convalescence. Later, others (42, 43) reported an in-
about the comprehensive, cohesive, but complex nature of the
creased peripheral conversion of thyroxine to reverse triiodo-
bodys metabolic responses to an acute febrile infection.
thyronine rT3, rather than to F3, and also, a concomitant decline
Catabolic losses of weight and muscle mass were most
in production of thyrotropin releasing hormone from higher
apparent clinically (5). Free amino acids were being liberated
brain centers (43).
from contractile muscle protein (5, 16, 26, 44-50). Many
amino acids were then taken up by the liver, by phagocytes, by
Pituitary gland
lymphocytes, and by other body cells (44-60). Some free
Other studies showed an increased pituitary secretion of amino acids were used to create new proteins, such as enzymes,
adrenocorticotropin hormone (ACTH) (14) as well as growth acute-phase plasma glycoproteins, and metallothioneins (18,
hormone during acute infections (31). Large bursts of growth 22, 29, 30, 4.4-SO, 55, 57). Many amino acids were used to
hormone secretion occurred during glucose infusions (39, 40). create glucose, the principal fuel required for fever-induced
Water retention during acute febrile infections appeared to hypermetabolism (44-50). The metabolic degradation or con-
result from increased secretion of antidiuretic hormone by the version of some free amino acids, such as tryptophan and
posterior pituitary gland (27). Secretion of antidiuretic hor- phenylalanine, was accelerated (15, 16, 22, 55). In gram-
mone could become inappropriately large during some infec- negative infections an inhibition of lipoprotein lipase was
tions. found to cause large accumulations of triglycerides in plasma
(36, 37). A catabolic destruction or urinary loss of body vita-
Pancreas mins (3), best exemplified by vitamin A (60), once called the
Within hours after the initial onset of acute fever, fasting antiinfection vitamin (61), appears to contribute importantly to
plasma concentrations of both insulin and glucagon were both the morbidity and mortality of some infectious illnesses (62,
abnormally elevated (19, 38). This finding was quite remark- 63).
able because insulin and glucagon production typically shows
a reciprocal relation. Glucose tolerance tests, performed during THE ACUTE-PHASE RESPONSE
the very early hours of acute fever, had already become abnor-
mal, with patterns resembling those seen in adult-onset diabe- By the late 1960s, the bodys overall response to febrile
tes (19, 38). The administered glucose caused abnormally large infections was proving to represent a stereotyped admixture of
816 BEISEL

concomitant anabolic and catabolic events. When each mdi- sizable quantities by biotechnologic methods. It now seems
vidual response was plotted longitudinally, in comparison to evident that our crude LEM preparations contained other prom-
the fever curve, a distinct pattern emerged. Some metabolic flammatory cytokines in addition to IL-i (66, 67, 69).
responses began in the incubation period, some at the onset of We thus were introduced into the world of cytokines, a world
fever, some late in fever, and some during convalescence (5). that keeps expanding, even though the individual actions of
No matter which microorganism was causing an acute, gener- cytokines, and their interrelations are still incompletely under-
alized, febrile infection, the onset of most metabolic, biochem- stood. Acute-phase responses are initiated and controlled by
ical, or physiologic responses seemed to occur at relatively the proinflammatory cytokines (64, 66, 67, 69-74), including
consistent, predictable times during the course of illness. These IL-l, IL-6, IL-8, and tumor necrosis factor (TNF). The cyto-
many responses could be categorized temporally by their rela- kine interferon-a can also contribute to the wasting syndrome
tions to the time of onset of clinical symptoms and fever (5). In
of acute infections (75). Although numerous stimuli can initiate
fact, virtually every metabolic or biochemical process under
the cellular production of proi nflammatory cytokines, bacterial
investigation was found to be influenced in some manner by
endotoxins are somewhat unique because they primarily stim-
the bodys response to an acute infection.
ulate the release of TNF. As one of its actions, TNF inhibits
In todays terminology, this overall response is termed an
lipoprotein lipase enzymes, thus accounting for the high
acute-phase response (64), an acute-phase reaction, or the
plasma concentrations of triglycerides that develop during
systemic inflammatory response syndrome (65). This acute-
gram-negative sepsis (34, 36, 37).
phase response accompanies other severe medical and surgical
problems, in addition to infection (64).
This complex response, which also activates complement

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and stimulates the immune system, appears to help defend the CURRENT CONCEPTS CONCERNING
body (5, 64). However, on the darker side, acute-phase re- PROINFLAMMATORY CYTOKINES
sponses generate important nutritional costs (5), costs that can
produce severe, life-threatening malnutrition. In addition, Because acute-phase reactions have such high nutritional
acute-phase responses which become excessive or overly pro- costs (5, 76), new findings about the cytokines have potentially
longed can lead to hypotensive shock, multiple organ disfunc- great nutritional importance.
tion, and death (64-66).
Control mechanisms for cytokine actions

Like hormones. proinflammatory cytokine actions are regu-

DISCOVERY OF THE LEUKOCYTIC ENDOGENOUS lated by many checks and balances, as shown in Figure 2. To
MEDIATOR INTERLEUKIN 1 act on a cell, a cytokine must first attach itself to a protein
receptor on the cell surface. But cells produce many of these
As noted previously, endocrine responses could not explain receptor proteins that are then released to float free in plasma
or account for our emerging concepts about the acute-phase
(77, 78), where they can intercept and inactivate the matching
reaction and all its complexities.
cytokine. Other unique plasma protein molecules, receptor
Accordingly, we set out to see whether some unknown
antagonists, can block cellular receptors for specific cytokines
hormone-like substances were causing these acute-phase re-
(77, 78). And other cytokines such as IL-4 and IL-lO can
sponses (54). Sure enough, when a milliliter of sterile plasma
suppress the cellular production of proinflammatory cytokines
from an infected human being or laboratory animal was in-
(79-81).
jected into a normal test rat, signs of an acute-phase response
were initiated within minutes (50, 51, 54, 56, 57, 67). The
response-initiating, hormone-like substances we detected in Cytokine assay in biological fluids
plasma during acute infections were quite heat-labile (68).
Individual components of this complex system of checks and
Therefore, they were not bacterial lipopolysaccharide endotox-
balances can now be measured in plasma, and their relations
ins (67, 68). Rather, they proved to be small proteins. We could
can he studied throughout the course of an acute-phase reaction
detect them in large quantities in chemically induced sterile
(66, 69, 72, 78). These cytokines and their free receptors have
exudates (54, 67, 68). Accordingly, we named these newly
also been found in mucosal fluids as well as in plasma (82-84).
detected substances leukocytic endogenous mediators, or
Raqib et al (84) recently reported longitudinal measurements of
LEMs (54).
cytokines and receptor antagonists in the plasma and stools of
Although our crude LEMs met the technical definitions for
hormones. LEMs were produced by diverse types of individual patients with acute shigellosis. Concentrations of TNF-a, IL-
cells rather than by an anatomically defined glandular organ. 113, IL-6, IL-8, and IL-i receptor antagonist in stools were
For many years, before the advent of modern-day biotechnol- quite high when shigellosis patients were first seen, and grad-
ogy, LEMs were difficult to isolate, purify, identify, or quan- ually returned to normal values during the next 2 wk (84). We
titate. The precise amino acid sequence of LEMs remained still do not understand the pathogenic effects of these interact-
undefined. But eventually, our metabolically important LEMs ing molecules in either systemic or localized diseases. Findings
were equated with the endogenous pyrogens studied by fever like those of Raqib et al (84) raise yet unanswered questions
physiologists, and with the immunologists lymphocyte acti- about the potential role of cytokines, if any, in the pathogenesis
vating factor, and all were renamed interleukin I (IL-i) (64, of cholera and other secretory diarrheas. where nutrient losses
66). A still-growing number of other interleukins were discov- are initiated by the actions of a specific intestinal toxin, rather
ered, and in major breakthroughs, they were then produced in than by a generalized acute-phase reaction.
 INFECTION-INDUCED MALNUTRITION 817

sites it may help to eliminate. Already, a complete enteral

formula supplemented with arginine has shown amazing effi-
Macrophage/MonocYte cacy in shortening the duration of severe sepsis in intensive
care patients (65).

St imu 1 CYTOKINE-INDUCED VERSUS STARVATION-

INDUCED MALNUTRITION

The acute-phase reaction and its cytokine-driven hyperme-

cull S\< Activated

Macrophage/MOnOCYte
taholism
aware
being considered.
have
of these
high nutritional
costs whenever
costs
the
(5,
genesis
75, 76). One must
of malnutrition
be
is

The nutritional costs of cytokine-induced malnutrition dur-

Proinflananatory .Cytokine Synthesis
Cytokines Inhibitory Factor ing infection, as depicted in Table 1, differ in every way from
IL-i, IL-6, IL-B IL-b
TNF those due to uncomplicated starvation. A large number of
Cytokine Receptor
physiologic and metabolic processes react differently during
/ Antagonist uncomplicated starvation than during infection.
Cytokine-induced malnutrition is initiated by hypermetabo-
lism (5, 76), with its high basal metabolic rates. Body nitrogen
and other elements are lost quickly, while body water and

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sodium are being retained (5). Glucose and urea synthesis are
both increased during cytokine-induced malnutrition, but ke-
tone production is slowed (5). Oxidation of branched-chain
amino acids is increased, and acute-phase plasma glycoproteins
are created (5). And last, the immune system is activated. In
each instance, an opposite response is typical of uncomplicated
starvation.
Because starvation is rarely uncomplicated in infants and
children, any resultant malnutrition is generally influenced
importantly by cytokine-induced components. All of these
FIGURE 2. Concepl of the interacting factors that provide a system of many pathogenic differences must be taken into consideration
checks and balances for the proinflammatory cytokines. IL, interleukin; whenever malnutrition is being studied, treated, or considered
TNF, tumor necrosis factor. for public health interventions.
Time does not permit more than a passing, final mention of
Possible therapeutic role for using or controlling the other important aspect of the interaction between infection
cytokines and malnutrition, ie, the devastating effects of cytokine-in-
duced malnutrition on the immune system. Generalized and/or
Biotechnologically produced cytokines are being tested for
specific deficiencies of required nutrients (4, 6) can result in
their possible therapeutic uses, as are a variety of anticytokine
nutritionally acquired immunodeficiency syndromes, or
molecules, including specific antibodies (66), soluble cytokine
NAIDS (61). The synergism between NAIDS and infectious
receptors (85, 86), and novel cytokine-binding proteins (87).
diseases not only causes an estimated 30 000 childhood deaths
Anything such new approaches to therapy can do to modulate
a day worldwide, this synergism is also a major cause of deaths
or reduce the nutrient-losing effects of acute-phase reactions
in seriously ill patients in our most modern hospitals (61). No
will help to minimize cytokine-induced malnutrition.

Cytokine-induced generation of nitric oxide from TABLE 1

arginine Differences in the pathogenesis of malnutrition

In recent years, proinflammatory cytokines have been shown Starvation-induced Cytokine-induced

to influence another important area where nutrition and host
Basal metabolic rate Decreased Increased
defense seem to interact. These cytokines activate nitric oxide
Body nitrogen Conserved Lost quickly
synthase in leukocytes (88-90). Nitric oxide synthase is an
Body water Lost Retained
enzyme which oxygenates one of the guanido nitrogen groups
Body sodium Lost Retained
of arginine to produce citrulline and nitric oxide (88). The Glucose synthesis Inhibited Stimulated
December 18th issue of Science, in 1992, (91) named NO the Ketone synthesis Stimulated Inhibited
Molecule of the Year, using the catch phrase Just Say NO. Urea synthesis Reduced Increased
Among its many important biological effects, NO has proven Muscle BCAA oxidation Minimized Increased
to be a highly potent microbiocidal and tumoricidal agent. The Acute-phase plasma proteins Unchanged Produced
importance of NO in this regard may rival that of the more rapidly
Antimicrobial defenses Unchanged or Activated
familiar free oxygen radicals in potency and effectiveness.
weakened
Much more needs to be learned about the cellular production of
NO in humans, and the varieties of microorganisms and para- I BCAA, branched-chain amino acid.
818 BEISEL

other cause of human mortality can match that of NAIDS. But 23. Shambaugh GE III, MacNair DS, Beisel WR. Small-bowel epithelial
unlike our current epidemic of virally induced AIDS, NAIDS migration during a generalized nonenteric infection in the rat. Am J

can be reversed by appropriate nutritional support. A Dig Dis 1967:12:403-8.

24. Lust G, Beisel WR. Alterations of alkaline phosphatase in mouse
I thank and acknowledge the important contributions of my numerous tissues after experimental infection. Proc Soc Exp Biol Med 1967:124:
colleagues and collaborators throughout the years. and acknowledge the 812-6.
courage and dedication of the many Seventh-day Adventist and other 25. Kehoe J, 1.ust G, Beisel WR. Lymphoid tissue-corticosteroid interac-
research volunteers who participated in these studies. tion: an early effect on both Mg2 and Mn2 -activated RNA poly-
merase activities. Biochim Biophys Acta l969;174:76l-3.
26. Feigin RD. Klainer AS, Beisel WR, Hornick RB. Whole-blood amino
acids in experimentally induced typhoid fever in man. N Engl J Med
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