L-tryptophan Produced by Genetically Engineered Bacteria
Here is a selected sample of references on the disease Eosinophilia Myalgia that emerged in relation to the consumption of genetically engineered L-tryptophan apparently in 1989. 37 deaths and 1500 largely permanent cripplings were involved. The sample is given to illustrate that there is a large scientific literature on this and other biosafety issues and to incourage you to use Medline to follow developments that are being published in the scientific literature. The list has not been updated.
Medline is available through most biomedical libraries
and there may be a charge for non-students and faculty. But you may find
the charge justified.
Date: 31-May-98
Name: T29086_80a0076U
Database: MEDLINE <1985 to present>
Set Search
Results
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001 exp eosinophilia-myalgia syndrome/ci
96
002 exp eosinophilia-myalgia syndrome/
251
003 new england journal of medicine.jn.
15631
004 2 and 3
1
005 from 2 keep 3,5-9
6
006 exp eosinophilia-myalgia syndrome/
251
007 limit 6 to english language
220
008 from 7 keep 4,6,9-12,16-20,23,25-26,29,31-32,35-38,42,46,50-
54
009 8
54
<1>
[Use LINK to view the full text]
Unique Identifier
97475850
Authors
Sternberg EM.
Title
Intimidation of researchers by special-interest groups [letter;
comment].
Comments
Comment on: N Engl J Med 1997 Apr 17;336(16):1176-80
Source
New England Journal of Medicine. 337(18):1316; discussion
1316-7, 1997
Oct 30.
<2>
Unique Identifier
96163723
Authors
Kaufman LD. Krupp LB.
Title
Eosinophilia-myalgia syndrome, toxic-oil syndrome, and diffuse
fasciitis
with eosinophilia. [Review] [89 refs]
Source
Current Opinion in Rheumatology. 7(6):560-7, 1995 Nov.
Abstract
The similarity of eosinophilia-myalgia syndrome (EMS) and toxic-oil
syndrome (TOS) to systemic sclerosis and diffuse fasciitis with
eosinophilia (DFE) highlights the potential for environmental
agents to
induce autoimmune disease. Further, a candidate etiologic agent
for EMS,
3-(phenylamino)alanine, is chemically similar to the aniline
derivative
identified in samples of oil implicated in TOS,
3-(N-phenylamino)-1,2-propanediol, suggesting pathogenic overlap.
The
late-stage manifestations of EMS and TOS are muscle cramping,
arthralgia,
severe fatigue, and cognitive impairment. This review focuses
on the
divergent and parallel findings in EMS, TOS, and DFE. The formation
of the
Environmentally Associated Connective Tissue Disease Study Group
within
the American College of Rheumatology will provide a forum for
the
development of registries to study suspected toxin-induced disorders.
[References: 89]
<3>
Unique Identifier
98042421
Authors
Williamson BL. Tomlinson AJ. Naylor S. Gleich
GJ.
Title
Contaminants in commercial preparations of melatonin [letter].
Source
Mayo Clinic Proceedings. 72(11):1094-5, 1997 Nov.
<4>
Unique Identifier
97439681
Authors
Williamson BL. Benson LM. Tomlinson AJ. Mayeno
AN. Gleich GJ. Naylor
S.
Title
On-line HPLC-tandem mass spectrometry analysis of contaminants
of
L-tryptophan associated with the onset of the eosinophilia-myalgia
syndrome.
Source
Toxicology Letters. 92(2):139-48, 1997 Jul 21.
Abstract
The structural characterization of a number of contaminants
of
L-tryptophan (Trp) associated with eosinophilia myalgia syndrome
has been
performed for the first time by the powerful structural elucidation
technique of tandem mass spectrometry coupled with on-line HPLC
(LC-ESI-MS/MS). The identity of the contaminants: peaks UV-5,
3-(phenylamino)alanine, (PAA); E 1,1'-ethylidenebis(tryptophan);
200,
2-(3-indolylmethyl)-L-tryptophan; (all identified as case related)
and
peaks 1, 3-carboxy-1,2,3,4-tetrahydro-beta-carboline; 2,
3-carboxy-1-methyl-1,2,3,4-tetrahydro-beta-carboline; 100, 2-(2,3
dihydroxy-1-[3-indolyl]propyl)-L-tryptophan; and 300 and 400,
diastereomers of
3-carboxy-1-[3-indolyl-methyl]-1,2,3,4-tetrahydro-beta-carboline,
have
been confirmed by this technique. By comparison of tandem MS
(MS/MS) data
from these compounds with the MS/MS data of several other impurities,
we
have structurally characterized peaks CC, KK and OO, as well
as two
previously unreported components labeled as peak P18 and peak
P31. Peak
P18 was unresolved from the large Trp peak and has been characterized
as
indole-3-ethylamine. Peak P31 was previously unresolved from
peak 200, a
case related compound and therefore its structure is of extreme
importance. This compound has been tentatively identified as
2-(3-indolyl)-L-tryptophan.
<5>
Unique Identifier
97356945
Authors
Blackburn WD Jr.
Title
Eosinophilia myalgia syndrome [see comments]. [Review] [53 refs]
Comments
Comment in: Semin Arthritis Rheum 1997 Jun;26(6):781-4
Source
Seminars in Arthritis & Rheumatism. 26(6):788-93,
1997 Jun.
Abstract
The term eosinophilia myalgia syndrome (EMS) was coined in 1989
after a
cluster of cases with symptoms of incapacitating myalgias and
eosinophilia
were reported. This syndrome has been only defined as varying
degrees of
myalgias and peripheral eosinophilia. Case reports of EMS are
protean and
do not show a consistent clinical picture, raising the question
of whether
this reflects a single disorder or is a conflation of various
disorders.
There have been only two studies evaluating the association
of EMS with
1-tryptophan. These two included only 23 patients with EMS.
Apart from the
obvious statistical fragility inherent in such small studies,
each is
further weakened by differences in the mechanisms by which patients
and
controls were selected. Furthermore, the continued reports of
EMS after
1-tryptophan was removed from the market raise additional questions
about
the association. Nonetheless, there has been an inordinate reliance
on a
history of 1-tryptophan ingestion in making the diagnosis of
EMS. When
presented case studies, clinicians were much more likely to
make the
diagnosis of EMS when a history of 1-tryptophan ingestion was
included.
These observations underscore the need for careful application
of
well-considered diagnostic criteria to the study of new syndromes
and
their potential associations. [References: 53]
<6>
Unique Identifier
97356943
Authors
Espinoza LR.
Title
The eosinophilia myalgia syndrome: to be or not to be [editorial;
comment]. [Review] [40 refs]
Comments
Comment on: Semin Arthritis Rheum 1997 Jun;26(6):788-93
Source
Seminars in Arthritis & Rheumatism. 26(6):781-4, 1997
Jun.
<7>
Unique Identifier
97338985
Authors
Hess EV.
Title
Eosinophilia-myalgia syndrome: opportunities realized and missed
[letter;
comment].
Comments
Comment on: J Rheumatol 1996 Oct;23(10):1679-81, Comment on:
J Rheumatol
1996 Oct;23(10):1682-5, Comment on: J Rheumatol 1996 Oct;23(10):1784-7
Source
Journal of Rheumatology. 24(6):1239-40, 1997 Jun.
<8>
Unique Identifier
97305440
Authors
Buss WC. Stepanek J. Bankhurst AD. Mayeno
AN. Pastuszyn A. Peabody D.
Title
EBT, a tryptophan contaminant associated with eosinophilia myalgia
syndrome, is incorporated into proteins during translation as
an amino
acid analog.
Source
Autoimmunity. 25(1):33-45, 1996.
Abstract
The tryptophan dimer 1,1'-ethylidenebis[L-tryptophan] was identified
as a
contaminant of tryptophan preparations associated with
Eosinophilia-Myalgia Syndrome. In this paper, we describe experiments
examining the hypothesis that 1,1'-ethylidenebis[L-tryptophan]
acts as an
amino acid analog replacing L-tryptophan during the synthesis
of proteins.
We propose further that proteins containing
1,1'-ethylidenebis[L-tryptophan] are rejected in an autoimmune
process
identified clinically as Eosinophilia-Myalgia Syndrome. Rabbit
reticulocyte lysates containing an estimated 1 microM L-tryptophan
were
used to assay the ability of 1,1'-ethylidenebis[L-tryptophan]
to compete
with 3H-L-tryptophan for incorporation into proteins translated
from BMV
RNA. 1,1'-Ethylidenebis[L-tryptophan] in concentrations of 40,
80 and 110
microM reduced lysate 3H-L-tryptophan incorporation to 81%,
76% and 75% of
control incorporation obtained in the absence of
1,1'-ethylidenebis[L-tryptophan]. In the presence of 20 microM
L-tryptophan, 110 microM 1,1'-ethylidenebis[L-tryptophan] reduced
3H-L-tryptophan incorporation to 56% of control incorporation.
In
contrast, ethyl-L-tryptophan did not significantly reduce 3H-L-tryptophan
incorporation. In the presence of 110 microM
1,1'-ethylidenebis[L-tryptophan] and 20 microM L-tryptophan,
3H-L-leucine
incorporation was not significantly reduced compared to incorporation
in
the absence of 1,1'-ethylidenebis[L-tryptophan], demonstrating
that
proteins were translated to full length during elongation. These
findings
suggest that 1,1'-ethylidenebis[L-tryptophan], but not ethyl-L-tryptophan,
reduced 3H-L-tryptophan incorporation into proteins by substituting
for
L-tryptophan rather than by causing premature termination or
significant
slowing of nascent protein chains.
<9>
Unique Identifier
97124940
Authors
Wagner KR. Elmore JG. Horwitz RI.
Title
Diagnostic bias in clinical decision making: an example of L-tryptophan
and the diagnosis of eosinophilia-myalgia syndrome.
Source
Journal of Rheumatology. 23(12):2079-85, 1996 Dec.
Abstract
OBJECTIVE: Eosinophilia-myalgia syndrome (EMS) has been defined
as the
clinical presentation of eosinophilia, severe myalgia, and the
exclusion
of other infectious/malignant illnesses. Since the case definition
does
not require exposure to L-tryptophan (LT), diagnostic bias would
occur if
a physician's decision to diagnose EMS were influenced by knowledge
of LT
use. METHODS: A random sample of 813 physicians practising in
the United
States and Canada was obtained. Physicians were asked to provide
diagnoses
for 6 case vignettes having diverse resemblances to EMS. Six
weeks later,
participants were asked to provide diagnoses for a complementary
series of
cases described in identical text except for different data
regarding LT
use. RESULTS: Physicians who responded (N = 227, 28%) were more
likely to
diagnose EMS when LT exposure was present compared to the same
case
without LT use. In the most striking difference, EMS was diagnosed
by 48%
of physicians when the case was described in a man using LT,
but by only
8% of physicians for the same case without LT use. The McNemar
bias
ratios, which compare responses provided by physicians completing
both
series, ranged from 0.65 to 1.0. CONCLUSION: These data indicate
that the
diagnosis of EMS may be biased by knowledge of LT. By showing
the presence
of diagnostic bias in clinical decision making, we suggest an
important
methodological problem that may arise in both clinical and research
settings.
<10>
Unique Identifier
97084408
Authors
Simat T. van Wickern B. Eulitz K. Steinhart
EH.
Title
Contaminants in biotechnologically manufactured L-tryptophan.
Source
Journal of Chromatography B: Biomedical Applications.
685(1):41-51, 1996
Oct 11.
Abstract
The epidemic outbreak of a new disease, the eosinophilia-myalgia
syndrome
(EMS), was traced back to the intake of L-tryptophan (Trp) of
certain lots
from a single manufacturer. Since some trace contaminants were
related to
EMS, it appeared to be necessary to identify and find the origin
of most
trace contaminants in the EMS related Trp in order to apply
this knowledge
to a prospective manufacturing practice. Seventeen contaminants
were
determined in an implicated Trp lot by a single reversed-phase
high-performance liquid chromatography run using UV and fluorescence
detection. Most of these contaminants were classified as Trp
metabolites,
non-physiological oxidation or carbonyl condensation compounds
of Trp. The
amount and the pattern of contaminants were compared with recently
manufactured Trp and Trp-containing preparations.
<11>
Unique Identifier
97062603
Authors
Steinhart H. van Wickern B. Meyer K. Simat
T.
Title
Synthesis and analysis of contaminants in ems-related tryptophan.
Source
Advances in Experimental Medicine & Biology. 398:667-75,
1996.
<12>
Unique Identifier
97062549
Authors
Nicolodi M. Sicuteri F.
Title
Eosinophilia myalgia syndrome. The role of contaminants, the
role of
serotonergic metabolism set up.
Source
Advances in Experimental Medicine & Biology. 398:351-7,
1996.
<13>
Unique Identifier
97062547
Authors
Hertzman PA.
Title
The eosinophilia-myalgia syndrome and the toxic oil syndrome.
Pursuing
parallels. [Review] [8 refs]
Source
Advances in Experimental Medicine & Biology. 398:339-42,
1996.
<14>
Unique Identifier
97062545
Authors
Sternberg EM.
Title
Pathogenesis of L-tryptophan eosinophilia myalgia syndrome.
[Review] [25
refs]
Source
Advances in Experimental Medicine & Biology. 398:325-30,
1996.
Abstract
Taken together, these studies suggest that many different etiologic
agents
alone or together may initiate the common final pathways of
tissue
pathologic response resulting in the clinical syndrome of eosinophilia,
myalgias and fasciitis. Tryptophan itself may contribute to
some of the
scarring features of the illness, while impure L-tryptophan,
and one or
more of the impurities cause the characteristic features of
the illness.
The altered tryptophan metabolism in EMS is secondary to inflammation.
[References: 25]
<15>
Unique Identifier
97050456
Authors
Kilbourne EM. Philen RM. Kamb ML. Falk H.
Title
Tryptophan produced by Showa Denko and epidemic eosinophilia-myalgia
syndrome [comment]. [Review] [22 refs]
Comments
Comment on: J Rheumatol Suppl 1996 Oct;46 :44-58; discussion
58-9, Comment
on: J Rheumatol Suppl 1996 Oct;46 :60-72
Source
Journal of Rheumatology - Supplement. 46:81-8; discussion
89-91, 1996
Oct.
Abstract
Evidence from an array of scientific studies strongly supports
the
conclusion that ingestion of products containing L-tryptophan
(LT)
produced by Showa Denko KK caused the 1989 epidemic of
eosinophilia-myalgia syndrome (EMS) in the United State. In
case-control
studies of EMS, LT exposure was essentially universal among
cases but rare
among controls. Of 6 manufacturers of LT, only LT manufactured
by Showa
Denko KK was clearly associated with illness. The data meet
other Hill
criteria for inferring a causal relationship. Consistent findings
were
found in multiple independently conducted studies. There was
a
dose-response effect, with risk of illness increasing as a function
of the
amount of tryptophan consumed. The extremely small p values
observed in
the multiple independently conducted studies effectively rule
out the
possibility that the tryptophan-EMS association was the result
of chance.
Moreover, no potential confounding factor or bias explains the
association. The incidence of EMS in the United States diminished
abruptly
once LT containing products were recalled. [References: 22]
<16>
Unique Identifier
97050454
Authors
Horwitz RI. Daniels SR.
Title
Bias or biology: evaluating the epidemiologic studies of L-tryptophan
and
the eosinophilia-myalgia syndrome [see comments].
Comments
Comment in: J Rheumatol Suppl 1996 Oct;46 :81-8; discussion
89-91
Source
Journal of Rheumatology - Supplement. 46:60-72, 1996 Oct.
Abstract
When investigating the cause of a chronic disease, epidemiologists
are
forced to substitute observational, nonexperimental methods
such as cohort
or case-control studies for the scientifically preferred "gold
standard,"
the randomized controlled trial. Because neither cohort nor
case-control
studies are done under experimental conditions, the results
may not
accurately reflect those that would be found in a randomized
experiment.
Before the results of epidemiologic research can be used for
inference
regarding a cause of disease, it is necessary to examine the
design and
conduct of such studies to ensure their results could not have
been
distorted by potential sources of bias. We evaluate the epidemiologic
studies of the relationship between intake of L-tryptophan (LT)
and the
occurrence of eosinophilia-myalgia syndrome (EMS) from information
provided in the published reports and underlying data and documentation
of
the studies obtained from the US Centers for Disease Control
and state
health departments. We reviewed separately the initial 2 studies
that
examined the link between LT and the risk for EMS and the subsequent
studies that focused on the specific manufacturing process or
chemical
constitutents of LT that might have been responsible for EMS.
The 2
initial studies compared cases of EMS with controls who were
asymptomatic.
The investigators concluded that ingestion of LT was associated
with the
occurrence of EMS. However, these studies contained methodologic
problems,
including diagnostic bias, publicity, recall and reporting bias,
bias in
the inclusion and exclusion of cases and controls, inequalities
between
cases and controls in the indications for the use of LT, and
failure to
ensure that the exposure to LT preceded the onset of symptoms
of EMS.
These potential biases make it difficult to use the data derived
from
these investigations to justify a causal inference. Subsequent
studies
were conducted under the assumption that there was a valid association
between ingestion of LT and the occurrence of EMS. These studies
focused
on tracing back LT to the manufacturer. These studies also had
a variety
of methodologic shortcomings, including problems in the assembly
of study
subjects leading to the selected samples of cases and controls,
the lack
of information on the brand and lot of LT for many subjects,
multiple
brand use, differences in the timing of exposure between cases
and
controls, the difficulty of the process of tracing LT products
to the
appropriate manufacturer, inconsistent classification of symptoms
depending on brand of LT used, and inconsistencies in the traceback
procedures between cases and controls. In light of these analyses,
it
appears that the cause of EMS has not been definitively identified.
The
search for the cause of EMS should continue without the underlying
assumption that LT or some contaminant is responsible.
<17>
Unique Identifier
97050453
Authors
Shapiro S.
Title
Epidemiologic studies of the association of L-tryptophan with
the
eosinophilia-myalgia syndrome: a critique [see comments].
Comments
Comment in: J Rheumatol Suppl 1996 Oct;46 :81-8; discussion
89-91
Source
Journal of Rheumatology - Supplement. 46:44-58; discussion
58-9, 1996
Oct.
Abstract
In 1989 and 1990, 2 reports of a new disease labeled the
eosinophilia-myalgia syndrome (EMS) and attributed to L-tryptophan
(LT)
were published. In subsequent studies a putative contaminant
was
implicated. In this review the following studies are considered:
the
initial 2 reports of the overall association, one report of
an association
between LT and eosinophilic fasciitis, and one report describing
the scale
of the apparent epidemic of LT induced EMS. Of the 2 initial
studies, one
included previously reported exposed cases, failed to rule out
the
possibility that early symptoms of EMS could have caused LT
use rather
than the reverse, and failed to adhere to the methods, as published.
The
2nd study has not been published in a peer reviewed journal.
The study of
eosinophilic fasciitis was subject to information bias and
misclassification of the timing of LT use. The apparent epidemic
could
have been an artefact of waxing and waning enthusiasm for reporting
exposed cases to an EMS registry, corresponding with the timing
and the
amount of publicity given to the topic. The questionable validity
of these
studies considerably weakens the claim that LT or a contaminant
caused
EMS.
<18>
Unique Identifier
97050447
Authors
Clauw DJ. Pincus T.
Title
The eosinophilia-myalgia syndrome: what we know, what we think
we know,
and what we need to know. [Review] [26 refs]
Source
Journal of Rheumatology - Supplement. 46:2-6, 1996 Oct.
<19>
Unique Identifier
97050431
Authors
Sullivan EA. Staehling N. Philen RM.
Title
Eosinophilia-myalgia syndrome among the non-L-tryptophan users
and
pre-epidemic cases [see comments].
Comments
Comment in: J Rheumatol 1996 Oct;23(10):1679-81
Source
Journal of Rheumatology. 23(10):1784-7, 1996 Oct.
Abstract
OBJECTIVE: Eosinophilia-myalgia syndrome (EMS) has been associated
with
L-tryptophan (LT) use since 1989, but as yet no etiologic agent
has been
identified. We describe the non-L-tryptophan associated cases
of EMS, and
those patients with illness onset preceding the 1989 epidemic.
METHODS:
Review of all patients in the EMS national state based surveillance
system
administered by the Centers for Disease Control and Prevention
(CDC) who
satisfied the EMS surveillance case definition. RESULTS: Of
1345 persons
with EMS that satisfied the CDC surveillance case definition
for EMS, 26
(2%) persons reported not having used LT (non-LT). Persons who
did not use
LT were significantly younger (mean age 39 years; p = 0.02)
and were more
likely than LT users to have onset of their illness before the
EMS
epidemic (before July 1, 1989) (p < 0.001). Non-LT users
reported fewer
pulmonary symptoms but had rates of neuropathy and scleroderma-like
skin
changes similar to LT users. Non-LT users had lower mean eosinophil
counts
(5.6 x 10(9) cells/I LT users 6.2 x 10(9) cells/I), reported
no EMS
attributable deaths, but were hospitalized (48%) more often
than LT users
(34%). Of the 1345 EMS cases, 191 (14%) reported a pre-epidemic
illness
onset. Symptoms of peripheral edema, rash, scleroderma-like
skin change,
alopecia, and neuropathy were more prevalent in pre-epidemic
patients.
Mean eosinophil count was significantly higher for epidemic
patients than
for pre-epidemic patients (p = 0.004). CONCLUSION: Non-LT EMS
cases were
more likely to be younger and to have a pre-epidemic illness
onset of EMS,
but otherwise were similar to LT associated EMS cases. Pre-epidemic
EMS
cases were more likely to report the presence of neuropathy
and
scleroderma-like skin change, but not pulmonary symptoms, hospitalization,
or death.
<20>
Unique Identifier
97050411
Authors
Belongia EA. Gleich GJ.
Title
The eosinophilia-myalgia syndrome revisited [editorial].
Source
Journal of Rheumatology. 23(10):1682-5, 1996 Oct.
<21>
Unique Identifier
97050410
Authors
Hertzman PA.
Title
The eosinophilia-myalgia syndrome: opportunities realized and
missed
[editorial; comment].
Comments
Comment on: J Rheumatol 1996 Oct;23(10):1784-7
Source
Journal of Rheumatology. 23(10):1679-81, 1996 Oct.
<22>
Unique Identifier
96212397
Authors
Sullivan EA. Kamb ML. Jones JL. Meyer P.
Philen RM. Falk H. Sinks T.
Title
The natural history of eosinophilia-myalgia syndrome in a
tryptophan-exposed cohort in South Carolina.
Source
Archives of Internal Medicine. 156(9):973-9, 1996 May
13.
Abstract
BACKGROUND: In a previous study, we did follow-up on 418 patients
who were
exposed to tryptophan in 1989, of whom 47 (11%) had definite
and 63 (9%)
possible eosinophilia-myalgia syndrome (EMS). METHODS: We assessed
mortality and clinical spectrum of illness since 1989 for 242
(58%) of the
418 tryptophan-exposed patients from the original study. To
assess
outcomes, we used hospital and death records, interviewer-administered
questionnaires, physical examinations, and laboratory tests.
RESULTS:
During the follow-up interval, mortality from all causes was
19% in those
with definite EMS, 7% in possible EMS, and 3% in those who were
not ill.
The age- and sex-adjusted mortality in those with definite EMS
was more
than 3 times that of the general population or of tryptophan
users in the
practice who were not ill. Six deaths (66%) among the definite
EMS case
patients occurred during the 18 months immediately after symptom
onset.
Compared with the tryptophan users who were not ill, survivors
with
definite EMS continued to report excess morbidity for 6 major
EMS symptoms
(myalgia, arthralgia, weakness, rash, alopecia, and sclerodermiform
skin
changes), but they also reported that the symptom number and
severity
diminished with time. None of the tryptophan users who were
not ill in
1989 developed a symptom complex suggesting new EMS during the
follow-up
interval. CONCLUSIONS: This study assessing a tryptophan-exposed
population found those persons who developed EMS during the
1989 epidemic
were at increased risk for death, particularly early after disease
onset.
Survivors reported improvement or resolution of major symptoms,
suggesting
that the severity of EMS diminishes with time. We found no evidence
of
delayed onset of EMS in tryptophan users who were not ill in
1989,
regardless of the brand used.
<23>
Unique Identifier
97197492
Authors
Anonymous.
Title
Eosinophilia-Myalgia Syndrome: Review and Reappraisal of Clinical,
Epidemiologic and Animal Studies Symposium. Washington, D.C.,
USA,
December 7-8, 1994. Proceedings.
Source
Journal of Rheumatology - Supplement. 46:1-110, 1996 Oct.
<24>
Unique Identifier
96294077
Authors
James TN.
Title
1995 Bailey K. Ashford lecture. Public health lessons from two
catastrophic epidemics: the toxic oil syndrome and the
eosinophilia-myalgia syndrome.
Source
Puerto Rico Health Sciences Journal. 15(1):45-8, 1996
Mar.
<25>
Unique Identifier
96192233
Authors
Zangrilli JG. Mayeno AN. Vining V. Varga J.
Title
1,1'-Ethylidenebis[L-tryptophan], an impurity in L-tryptophan
associated
with eosinophilia-myalgia syndrome, stimulates type I collagen
gene
expression in human fibroblasts in vitro.
Source
Biochemistry & Molecular Biology International. 37(5):925-33,
1995 Nov.
Abstract
Eosinophilia-myalgia syndrome (EMS), a recently described inflammatory
disorder characterized by myalgia, peripheral eosinophilia,
and
multisystem inflammation is associated with L-tryptophan consumption.
Fibrosis of various tissues due to excessive accumulation of
type I
collagen is a prominent late manifestation of the syndrome.
1,1'-Ethylidenebis[L-tryptophan] (EBT), an impurity distinct
from
L-tryptophan found in case-associated lots, has been implicated
in
function in vitro. Incubation of confluent fibroblasts with
EBT, but not
its hydrolysis product 1-methyl-tetrahydro-beta-carboline-3-carboxylic
acid, caused a dose-dependent increase in collagen synthesis
and in type I
collagen mRNA levels independent of its effect on proliferation.
In
contrast, expression mRNA for fibronectin was not affected.
These findings
indicate that EBT stimulates type I collagen production by human
fibroblast, and suggest that EBT may be involved in the development
of
fibrosis in EMS.
<26>
Unique Identifier
96136143
Authors
Daniels SR. Hudson JI. Horwitz RI.
Title
Epidemiology of potential association between L-tryptophan ingestion
and
eosinophilia-myalgia syndrome. [Review] [64 refs]
Source
Journal of Clinical Epidemiology. 48(12):1413-27; discussion
1429-40,
1995 Dec.
Abstract
This article examines the methodology of the epidemiological
studies of
the association between L-tryptophan and eosinophilia-myalgia
syndrome
(EMS) and evaluates the validity of the conclusions from these
studies. In
the initial case-control studies of L-tryptophantryptophan and
EMS there
were a variety of methodological problems, including different
sources and
different exclusion criteria for cases and controls, which could
have
resulted in selection bias, as well as problems with information
bias and
confounding. The studies of manufacturer and brand also had
similar
potential for bias. The L-tryptophan-EMS association is based
on two small
studies that had important methodological inadequacies. Subsequent
studies
of brand of L-tryptophan also contained errors in design, which
may have
produced biased results and call the conclusions into question.
The cause
of eosinophilia-myalgia syndrome remains unknown. [References:
64]
<27>
Unique Identifier
96124948
Authors
Sato F. Hagiwara Y. Kawase Y.
Title
Subchronic toxicity of 3-phenylamino alanine, an impurity in
L-tryptophan
reported to be associated with eosinophilia-myalgia syndrome.
Source
Archives of Toxicology. 69(7):444-9, 1995.
Abstract
Consumption of certain product lots of L-tryptophan (LT) has
been reported
to be epidemiologically associated with an outbreak of
eosinophilia-myalgia syndrome (EMS) in the United States. Since
the
production lots were found to contain 3-phenylamino alanine
(PAA) as an
impurity, its effects were studied by administering the substance
orally
by gavage to 5-week-old Sprague-Dawley rats. Groups of animals
were given
PAA for 13 consecutive weeks at dose levels of 1, 10 and 100
mg/kg per
day. The animals were killed at 4 or 8 weeks. Hematological
and blood
biochemical tests were performed and detailed histopathological
observations were made. No significant abnormalities were observed
in the
test animals and in particular no EMS-like conditions. A brief
summary of
other animal studies using several species of rats and mice
performed in
our laboratory since 1989 on various LT related substances is
also
presented. No EMS-like effects were observed in these studies.
<28>
Unique Identifier
96120716
Authors
Mayeno AN. Benson LM. Naylor S. Colberg-Beers
M. Puchalski JT. Gleich
GJ.
Title
Biotransformation of 3-(phenylamino)-1,2-propanediol to
3-(phenylamino)alanine: a chemical link between toxic oil syndrome
and
eosinophilia-myalgia syndrome.
Source
Chemical Research in Toxicology. 8(7):911-6, 1995 Oct-Nov.
Abstract
During late 1989, the eosinophilia-myalgia syndrome (EMS) developed
as an
epidemic in the United States, with numerous additional cases
reported in
several other countries worldwide. Eight years earlier, a closely-related
disease, the toxic oil syndrome (TOS), occurred in Spain as
a massive
food-borne epidemic. Although EMS was linked to the ingestion
of tainted
L-tryptophan, and TOS to aniline-denatured rapeseed oil, the
etiologic
agent(s) responsible for both diseases remains undetermined.
Contaminants
in these foodstuffs are believed to have triggered the diseases.
Aniline
contaminants, including 3-(phenylamino)-1,2-propanediol (PAP),
have been
reported in oil used by patients who developed TOS. A related
aniline
derivative, 3-(phenylamino)-L-alanine (PAA), was recently isolated
from
L-tryptophan associated with the onset of EMS. Here, we demonstrate
the
biotransformation of PAP into PAA by both rat hepatocytes and
human liver
tissue. The structural characterization of PAA was unequivocally
determined using on-line HPLC coupled with atmospheric pressure
chemical
ionization tandem mass spectrometry (LC-APCI-MS/MS). This finding
is the
first reported chemical link between TOS and EMS and suggests
that these
two related diseases share a common etiology, namely, PAA.
<29>
Unique Identifier
95337265
Authors
D'Arcy PF.
Title
L-tryptophan: eosinophilia-myalgia syndrome. [Review] [45 refs]
Source
Adverse Drug Reactions & Toxicological Reviews. 14(1):37-43,
1995 Spring.
<30>
Unique Identifier
95245617
Authors
Spitzer WO. Haggerty JL. Berkson L. Davis
W. Palmer W. Tamblyn R.
Laprise R. Faith JM. Elmore JG. Horwitz RI.
Title
Continuing occurrence of eosinophilia myalgia syndrome in Canada.
Source
British Journal of Rheumatology. 34(3):246-51, 1995 Mar.
Abstract
Eosinophilia myalgia syndrome (EMS), was defined by the Centers
for
Disease Control (CDC) as eosinophilia > 1000 mm3 and incapacitating
myalgia without infection or neoplasm. Studies suggested that
use of
L-tryptophan (L-T), was a risk factor. We conducted a
pharmacoepidemiological survey in Canada where access to L-T
is limited.
Using the active surveillance method, a 100% sample of potentially
involved specialists and a 15% sample of family physicians from
Ontario
and Quebec were surveyed regarding treatment of patients with
severe
myalgia within the past year. Follow-up amplified clinical and
laboratory
information. Overall response rates were 61.4%. Thirty-eight
per cent of
respondents reported at least one patient. Of 6423 patients
assessed, 19
'definite' and 25 'possible' EMS cases were identified. Information
from
physicians did not suggest use of L-T in patients with definite
or
possible EMS. It was considered that the cases found an underestimate
of
the incidence of EMS. Its continuing occurrence in Canada brings
causal
interpretations of earlier studies into question.
<31>
Unique Identifier
95124981
Authors
Sidransky H.
Title
Eosinophilia-myalgia syndrome: a recent syndrome serving as
an alert to
new diseases ahead. [Review] [44 refs]
Source
Modern Pathology. 7(7):806-10, 1994 Sep.
Abstract
A recently recognized disease, the eosinophilia-myalgia syndrome,
is
described and presented as a new condition attributable to nutritional
toxicology. Its etiology is related to the ingestion of L-tryptophan,
manufactured by a single Japanese supplier who had modified
its production
system, which, though of high purity, contained in minute concentrations
a
number of contaminants or impurities. Patients with eosinophilia-myalgia
syndrome develop an eosinophilia with pathologic changes mainly
involving
skin, muscle, and connective tissue. The findings suggest an
autoimmune
response. Experimental studies with the implicated L-tryptophan
as well as
with some contaminants have as yet failed to develop a suitable
animal
model of eosinophilia-myalgia syndrome. Further studies are
needed to
unravel the pathogenesis of this complex syndrome. At present,
physicians
need to be cognizant of this recent syndrome and be aware that
other new
diseases, induced by nutritional toxicological alterations and
possibly
related to technicological developments, lie ahead. [References:
44]
<32>
[Use LINK to view the full text]
Unique Identifier
94366220
Authors
Shapiro S.
Title
L-tryptophan and eosinophilia-myalgia syndrome [letter; comment].
Comments
Comment on: Lancet 1994 Apr 23;343(8904):1035-7
Source
Lancet. 344(8925):817-9, 1994 Sep 17.
<33>
Unique Identifier
94354966
Authors
Mayeno AN. Gleich GJ.
Title
Eosinophilia-myalgia syndrome and tryptophan production: a cautionary
tale.
Source
Trends In Biotechnology. 12(9):346-52, 1994 Sep.
Abstract
An epidemic of a new disease, termed eosinophilia-myalgia syndrome,
occurred in the USA in 1989. This syndrome was linked to the
consumption
of L-tryptophan manufactured by a single company utilizing a
fermentation
process. All the findings indicate that the illness was probably
triggered
by an impurity formed when the manufacturing conditions were
modified.
This outbreak highlights the need for close monitoring of the
chemical
purity of biotechnology-derived products, and for rigorous testing
of such
products following any significant changes to the manufacturing
process.
<34>
Unique Identifier
94285583
Authors
Mayeno AN. Gleich GJ.
Title
The eosinophilia-myalgia syndrome: lessons from Germany [editorial;
comment].
Comments
Comment on: Mayo Clin Proc 1994 Jul;69(7):620-34
Source
Mayo Clinic Proceedings. 69(7):702-4, 1994 Jul.
<35>
Unique Identifier
94285566
Authors
Carr L. Ruther E. Berg PA. Lehnert H.
Title
Eosinophilia-myalgia syndrome in Germany: an epidemiologic review
[see
comments].
Comments
Comment in: Mayo Clin Proc 1994 Jul;69(7):702-3
Source
Mayo Clinic Proceedings. 69(7):620-5, 1994 Jul.
Abstract
OBJECTIVE: To review the epidemiologic features of eosinophilia-myalgia
syndrome (EMS) in Germany. DESIGN: We determined the incidence
of EMS in
Germany through May 1992 and analyzed the dose of L-tryptophan
used, the
duration of intake, and the concurrent medications. MATERIAL
AND METHODS:
All patients receiving L-tryptophan preparations in Germany
were already
under medical supervision before the onset of the disease; thus,
information on patient history and other potential risk factors
was
readily available. Because of the drug status of L-tryptophan
preparations, brands could be accurately traced back to suppliers
of raw
materials. Statistical differences in age and gender of patients,
dose of
L-tryptophan, eosinophil count, and skin involvement were sought
between
patients with and those without concurrent medications. RESULTS:
On the
basis of guidelines established by the Centers for Disease Control
and
Prevention, 105 patients fulfilled the criteria for EMS. No
apparent
correlation was found between the incidence of EMS and the dose
of
L-tryptophan or the duration of intake before onset of EMS.
Assessment of
the study group showed that 45% were taking various other medications,
whereas 55% were taking L-tryptophan only. Analysis by type
of
pharmaceutical agent showed no preponderance of a specific concurrent
drug
(in particular, psychotropic drugs). Thus, concurrently used
medications
did not seem to be an important variable. All cases of EMS were
associated
with L-tryptophan from formulators that had used raw materials
from the
previously implicated source. CONCLUSION: This study supports
the
pathophysiologic role of a contaminant in L-tryptophan in the
occurrence
of cases of EMS in Germany.
<36>
Unique Identifier
96053013
Authors
Brady LS. Page SW. Thomas FS. Rader JL.
Lynn AB. Misiewicz-Poltorak
B. Zelazowski E. Crofford LJ. Zelazowski P.
Smith C. et al.
Title
1,1'-Ethylidenebis[L-tryptophan], a contaminant implicated in
L-tryptophan
eosinophilia myalgia syndrome, suppresses mRNA expression of
hypothalamic
corticotropin-releasing hormone in Lewis (LEW/N) rat brain.
Source
Neuroimmunomodulation. 1(1):59-65, 1994 Jan.
Abstract
The L-tryptophan eosinophilia myalgia syndrome (L-Trp-EMS),
related to
ingestion of impure L-Trp, occurred in epidemic proportions
in the United
States in 1989. Epidemiologic studies implicated
1,1'-ethylidenebis[L-tryptophan] (EBT) as the impurity most
highly
associated with development of human L-Trp-EMS. We have previously
shown
that Lewis (LEW/N) rats fed L-Trp implicated in the L-Trp-EMS
epidemic
(case-associated L-Trp) develop fasciitis and perimyositis which
is
associated with a reduction in corticotropin-releasing hormone
(CRH) mRNA
expression in the hypothalamic paraventricular nucleus (PVN).
In this
study, we report the effects of EBT- and case-associated L-Trp
on CRH mRNA
expression in the hypothalamic PVN and secretion of adrenocorticotropic
hormone (ACTH) and corticosterone (CORT) into the plasma over
a time
course of 1-6 weeks in the same rats in which we have found
fascial
thickening and immune cell activation induced by these compounds.
Both
control L-Trp and EBT stimulated the secretion of ACTH and CORT
at 1-2
weeks, whereas case-associated L-Trp did not. EBT and case-associated
L-Trp decreased CRH mRNA expression in the PVN at 2-6 weeks,
while control
L-Trp had no effect. The striking contrast in the effects of
case-associated L-Trp and EBT on the HPA axis suggests that
the reduction
in CRH mRNA levels in the PVN seen in each case may be related
to
different mechanisms. It is possible that EBT suppresses CRH
mRNA
expression directly, in the absence of inflammation, while case-associated
L-Trp may act through multiple mechanisms, including that associated
with
inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)
<37>
Unique Identifier
95214011
Authors
Clauw DJ. Flockhart DA. Mullins W. Katz P.
Medsger TA Jr.
Title
Eosinophilia-myalgia syndrome not associated with the ingestion
of
nutritional supplements. [Review] [12 refs]
Source
Journal of Rheumatology. 21(12):2385-7, 1994 Dec.
Abstract
The eosinophilia-myalgia syndrome (EMS) is a recently recognized
illness
characterized by peripheral eosinophilia, myalgias, and a variety
of
neurologic, cutaneous, and pulmonary features. Most of those
afflicted
with this disorder consumed L-tryptophan, but some cases have
occurred in
association with the ingestion of other nutritional supplements.
We
describe someone who developed EMS in 1986 without the ingestion
of any
nutritional supplements. He was also found to have slowed P450
metabolism,
in a pattern seen in other patients with EMS. We postulate that
EMS can
occur in association with the ingestion of multiple substances
that share
minute quantities of a common, as yet unidentified, toxin(s),
and that
metabolic host factors may contribute to disease susceptibility.
[References: 12]
<38>
Unique Identifier
95213989
Authors
Michelson D. Page SW. Casey R. Trucksess MW.
Love LA. Milstien S.
Wilson C. Massaquoi SG. Crofford LJ. Hallett
M. et al.
Title
An eosinophilia-myalgia syndrome related disorder associated
with exposure
to L-5-hydroxytryptophan.
Source
Journal of Rheumatology. 21(12):2261-5, 1994 Dec.
Abstract
OBJECTIVE. To determine whether L-5-hydroxytryptophan (L-5-HTP)
associated
with eosinophiliamyalgia syndrome (EMS) like illness contains
impurities
in a fashion similar to that described in L-tryptophan associated
with
EMS. METHODS. Members of a family who became ill after exposure
to L-5-HTP
were evaluated at the National Institutes of Health. Data from
patients
with extended exposure to L-5-HTP were also examined. Samples
of L-5-HTP
were examined using high performance liquid chromatography.
RESULTS. One
member of the family had EMS, and 2 others had eosinophilia.
No patient in
the other group reviewed developed the syndrome, although 2
patients
developed eosinophilia. The L-5-HTP used by the family contained
an
impurity not present in samples from the other patient group.
After
replacement with L-5-HTP not containing this impurity, eosinophilia
in 2
family members resolved. CONCLUSION. Some L-5-HTP contains impurities
that
may be related to L-5-HTP associated EMS.
<39>
Unique Identifier
95213974
Authors
Kaufman LD. Izquierdo Martinez M. Gomez-Reino JJ.
Title
Toxic oil syndrome and eosinophilia myalgia syndrome: similar,
different
or the same disorder? [editorial].
Source
Journal of Rheumatology. 21(12):2177-8, 1994 Dec.
<40>
Unique Identifier
95158605
Authors
Kaufman LD.
Title
The evolving spectrum of eosinophilia myalgia syndrome. [Review]
[192
refs]
Source
Rheumatic Diseases Clinics of North America. 20(4):973-94,
1994 Nov.
Abstract
Eosinophilia myalgia syndrome (EMS) is a toxin-induced illness
that
provides a model for the understanding of idiopathic immune-mediated
diseases that have overlapping features. The clinical development
and
chronic sequelae of EMS, its relationship to related disorders,
and the
accumulating data suggesting an important role for immune mechanisms
in
the pathogenesis of this disease are reviewed in this article.
[References: 192]
<41>
Unique Identifier
93362641
Authors
Philen RM. Hill RH Jr. Flanders WD. Caudill
SP. Needham L. Sewell L.
Sampson EJ. Falk H. Kilbourne EM.
Title
Tryptophan contaminants associated with eosinophilia-myalgia
syndrome. The
Eosinophilia-Myalgia Studies of Oregon, New York and New Mexico.
Source
American Journal of Epidemiology. 138(3):154-9, 1993 Aug
1.
Abstract
Eosinophilia-myalgia syndrome (EMS) has been linked to ingestion
of
tryptophan contaminated with 1,1'-ethylidene-bis[L-tryptophan]
(EBT), but
other contaminants have received little study. The authors identified
101
lots of L-tryptophan that had been consumed either by persons
with EMS or
by asymptomatic tryptophan users and quantified the amounts
of EBT and
five other contaminants in each lot. After stratification of
case and
noncase lots by time of manufacture to adjust for the strong
sequential
pattern over time among case and noncase lots, higher EBT levels
were
still associated with a lot's case status, but the association
lacked
statistical significance (p = 0.120, odds ratio = 1.56, 95%
confidence
interval 0.758-3.23). While these findings do not rule out the
possibility
that EBT is the etiologic agent in EMS, they raise the possibility
that
other chemical contaminants in manufactured tryptophan modify
the effects
of EBT or that the causal agent of EMS is an entirely distinct
compound.
<42>
Unique Identifier
93267526
Authors
Back EE. Henning KJ. Kallenbach LR. Brix KA.
Gunn RA. Melius JM.
Title
Risk factors for developing eosinophilia myalgia syndrome among
L-tryptophan users in New York.
Source
Journal of Rheumatology. 20(4):666-72, 1993 Apr.
Abstract
Using a case-control study design, patients with eosinophilia
myalgia
syndrome (EMS) who had used L-tryptophan (LT) were compared
with LT users
who did not develop EMS. Of the 113 case patients and 95 controls
who had
used a retail brand that could be traced to a bulk LT producer,
all (100%)
case-patients and 69 (73%) controls used LT brands that were
traced to
Showa Denko K.K. (lower 95% CL = 10.0). Among the users of LT
produced by
Showa Denko K.K., the risk of EMS was greater for persons who
used LT
produced after December 1, 1988 (OR = 25.8, [95% CL = 7.1, 101.4]).
The
risk of developing EMS increased with increased dosage of LT,
increased
age, and use of LT as a sleeping aid. These epidemiologic data
support the
hypothesis that the etiologic agent in EMS is a contaminant
introduced
into LT products during production.
<43>
Unique Identifier
93233547
Authors
Mitchell N.
Title
L-tryptophan and eosinophilia-myalgia syndrome [letter; comment].
Comments
Comment on: Med J Aust 1993 Jan 4;158(1):51-5
Source
Medical Journal of Australia. 158(5):363-4, 1993 Mar 1.
<44>
Unique Identifier
93233077
Authors
Henning KJ. Jean-Baptiste E. Singh T. Hill
RH. Friedman SM.
Title
Eosinophilia-myalgia syndrome in patients ingesting a single
source of
L-tryptophan.
Source
Journal of Rheumatology. 20(2):273-8, 1993 Feb.
Abstract
OBJECTIVE. To estimate the attack rate for eosinophilia-myalgia
syndrome
and to identify potential risk factors for illness among patients
attending a New York City medical clinic, who purchased L-tryptophan
containing products produced exclusively by Showa Denko K.K.
METHODS. A
case-control design was used. Cases and controls purchased L-tryptophan
containing products at the medical clinic from July 1, 1989--December
1,
1989. All case-patients identified with illness onset during
the study
period were included. Controls were selected by a systematic
sample of the
683 purchasers of L-tryptophan attending the same clinic. RESULTS.
Twelve
(2.2%) of an estimated 553 L-tryptophan users were case-patients.
Multivariate analysis suggested that lot 2 use (adjusted odds
ratio [OR] =
35.9), concomitant use of chromium (adjusted OR = 12.3), and
concomitant
use of pyridoxine (adjusted OR = 5.8) were associated with the
development
of illness. Chemical analysis of tablets corresponding to the
3 Showa
Denko K.K. lots ingested by study participants showed that lot
2 had the
highest concentration of ethylidenebis (L-tryptophan), a proposed
causative agent or marker for a causative agent in the
eosinophilia-myalgia syndrome. CONCLUSIONS. Information from
our study of
persons exposed to implicated L-tryptophan supports the role
for a
contaminant as the causative agent in the eosinophilia-myalgia
syndrome
and identifies possible cofactors that deserve further study.
<45>
Unique Identifier
93199703
Authors
Kaufman LD. Philen RM.
Title
Tryptophan. Current status and future trends for oral administration.
[Review] [65 refs]
Source
Drug Safety. 8(2):89-98, 1993 Feb.
<46>
Unique Identifier
93139603
Authors
Varga J. Jimenez SA. Uitto J.
Title
L-tryptophan and the eosinophilia-myalgia syndrome: current
understanding
of the etiology and pathogenesis. [Review] [66 refs]
Source
Journal of Investigative Dermatology. 100(1):97S-105S,
1993 Jan.
Abstract
The eosinophilia-myalgia syndrome (EMS) is a newly recognized
illness that
occurred in an epidemic form during the summer of 1989. The
illness was
characterized in the acute phase by myalgia and eosinophilia,
followed in
many patients by chronic cutaneous lesions, progressive neuropathy,
and
myopathy. EMS was associated with ingestion of L-tryptophan,
an essential
amino acid marketed as a nutritional supplement but widely used
as a
therapeutic agent. Evidence of abnormal L-tryptophan metabolism
has been
described in patients with EMS, and most likely reflects increased
activity of indoleamine 2,3-dioxygenase, the rate-limiting enzyme
of
tryptophan metabolism. A contaminant identified in EMS-associated
L-tryptophan preparations has been isolated and characterized,
but its
biologic effects and role as the etiologic agent in EMS remain
to be
established. Pathologic observations and experimental studies
indicate
that eosinophils, mononuclear inflammatory cells, and fibroblasts
are
potential effector cells, and interleukin-5 and transforming
growth
factor-beta are important mediators in the pathogenesis of the
syndrome.
Although few new cases of EMS occurred following the withdrawal
of
L-tryptophan, affected patients continue to manifest late sequelae
of the
disease, including dermal fibrotic conditions. This tragic outbreak
of a
newly recognized illness has focused interest on the role of
chemical and
environmental agents in the pathogenesis of various idiopathic
illness
characterized by tissue inflammation and fibrosis. [References:
66]
<47>
Unique Identifier
94125388
Authors
Swygert LA. Back EE. Auerbach SB. Sewell LE.
Falk H.
Title
Eosinophilia-myalgia syndrome: mortality data from the US national
surveillance system [see comments].
Comments
Comment in: J Rheumatol 1993 Oct;20(10):1644-6
Source
Journal of Rheumatology. 20(10):1711-7, 1993 Oct.
Abstract
OBJECTIVE. To describe some of the most severe features of
eosinophilia-myalgia syndrome (EMS) and identify potential prognostic
indicators. METHODS. Systematic review of data from initial
case reports
and from followup supplemental death report forms forwarded
to the
national surveillance system administered by the US Centers
for Disease
Control (CDC). RESULTS. As of August 10, 1991 36 deaths related
to EMS had
been reported to CDC. Among all patients fitting the surveillance
case
definition for EMS, we found that patients who died were older,
had higher
absolute leukocyte and eosinophil counts, and reported a greater
frequency
of cough or dyspnea, neuropathy, hepatomegaly, leukocytosis,
and elevated
erythrocyte sedimentation rate. All patients who died had illnesses
affecting multiple organ systems. Of the 36 patients who died,
33 (92%)
had neuromuscular sequelae, 29 (81%) had pulmonary complications,
and 23
(64%) had cardiac manifestations. The most commonly observed
disease
process leading to death was progressive polyneuropathy and
myopathy (24
of the 36 reported deaths) which produced complications of pneumonia
and
sepsis or respiratory failure due to weakness; cardiomyopathy
was the
underlying cause of death for 4 patients, primary pulmonary
disease for 3,
sudden death attributed to arrhythmia for 2, stroke for 2, and
septic
complications of therapy for one. CONCLUSION. Although neuromuscular
complications were the most prominent sequelae among patients
reported to
have died, this is clearly a multisystemic disease. Older age
and
involvement of more than one organ system suggest a particularly
poor
prognosis, and the neuromuscular, pulmonary and cardiovascular
sequelae
appear to be the most worrisome.
<48>
Unique Identifier
93170435
Authors
Kilbourne EM.
Title
Eosinophilia-myalgia syndrome: coming to grips with a new illness.
Source
Epidemiologic Reviews. 14:16-36, 1992.
Abstract
In late October 1989, over 1,500 cases of an unusual illness
involving
severe myalgia and striking peripheral eosinophilia were reported
in the
United States and several other countries. Other clinical manifestations
included pulmonary involvement (interstitial infiltrates and
pleural
effusions), skin rash and edema, axonal polyneuropathy, perimyositis,
and
possible adverse neurocognitive effects. Because of the primary
manifestations of the illness, it was named "eosinophilia-myalgia
syndrome" (EMS) by the Centers for Disease Control. Epidemiologic
studies
clearly linked illness to the ingestion of tryptophan produced
by a single
manufacturer in Japan, and the time course of the epidemic was
most
consistent with its being caused by a product contaminant. Epidemiologic
analysis of plant operating conditions and data obtained from
chemical
analyses of case- and control-associated lots implicated
1,1'-ethylidene-bis(tryptophan) (EBT) as a candidate for the
compound that
causes EMS. However, the etiologic significance of EBT is still
uncertain.
Factors found to increase a person's risk for EMS included higher
tryptophan dose and older age. Although cases occurred predominantly
in
women and patients had frequently been taking other medications
concurrently with tryptophan, sex and use of several categories
of other
medications were not shown to influence the risk of illness.
Few patients
recovered rapidly and fully from the disease. Many were treated
with
glucocorticoid medications, and although they may have benefited
from
therapy in the short term, the development of chronic sequelae
of EMS
appears not to have been prevented. Public health practitioners
currently
depend on the reports of alert clinicians to detect this type
of outbreak.
In this case, state and federal government epidemiologists,
once they were
notified, were able to develop substantial basic information
about the
epidemic in a relatively short time. Control measures were introduced
rapidly, effectively stopping the epidemic.
<49>
Unique Identifier
93021512
Authors
Nightingale SL.
Title
From the Food and Drug Administration.
Source
JAMA. 268(14):1828, 1992 Oct 14.
<50>
Unique Identifier
92366057
Authors
Keating JP. Wardill K. Viggiano J.
Title
Eosinophilia-myalgia syndrome associated with ingestion of L-tryptophan.
Source
New Zealand Medical Journal. 105(939):317, 1992 Aug 12.
<51>
Unique Identifier
92162075
Authors
Hibbs JR. Mittleman B. Hill P. Medsger TA
Jr.
Title
L-tryptophan-associated eosinophilic fasciitis prior to the
1989
eosinophilia-myalgia syndrome outbreak.
Source
Arthritis & Rheumatism. 35(3):299-303, 1992 Mar.
Abstract
OBJECTIVE. To investigate the relationship between L-tryptophan
(LT)
ingestion and eosinophilic fasciitis (EF) occurring prior to
the outbreak
of eosinophilia-myalgia syndrome in 1989. METHODS. Interviews
and record
reviews of 45 EF case-patients and 126 polymyositis patients
(controls)
diagnosed prior to 1988. RESULTS. Nine case-patients (20%) and
no controls
recalled taking LT before onset of the disease (odds ratio =
infinity, 95%
confidence interval = 8.3-infinity). Among EF case-patients,
LT ingestion
was associated with dyspnea. CONCLUSION. LT ingestion was associated
with
EF prior to the 1989 outbreak of eosinophilia-myalgia syndrome.
Lung
abnormalities may be a distinguishing feature of LT-mediated
illness.
<52>
Unique Identifier
92293658
Authors
Patmas MA.
Title
Eosinophilia-myalgia syndrome not associated with L-tryptophan.
Source
New Jersey Medicine. 89(4):285-6, 1992 Apr.
Abstract
The author reports a case of eosinophilia-myalgia syndrome (EMS),
not
associated with the use of tryptophan. Other nutritional supplements
should be considered as possible etiologic agents in EMS. Further
research
in this area is needed.
<53>
Unique Identifier
92067146
Authors
Shishikura T. Tsuchiya T. Sato F. Oguro K.
Ebisawa H.
Title
Eosinophilia caused by administration of L-tryptophan to animals
with
adrenal dysfunction.
Source
Toxicology Letters. 58(3):315-21, 1991 Nov.
Abstract
We have investigated an animal model of eosinophilia-myalgia
syndrome
(EMS), a disease that occurred in various parts of the United
States in
1989, with a view to determining its cause. We speculated that
adrenal
dysfunction might have potentially contributed to the occurrence
of EMS
and studied the effects of adrenal dysfunction on the eosinophil
count in
peripheral blood by using rats and mice whose adrenals had been
excised or
that had been metyrapone-treated, and giving them L-tryptophan.
As a
result, a significant increase in the eosinophil count was observed
in
both animal species. The results suggest that EMS may have been
caused,
not by L-tryptophan alone, but by the combined effects of adrenal
dysfunction and L-tryptophan ingestion.
<54>
Unique Identifier
92018203
Authors
Aldhous P.
Title
Biotechnology. Yellow light on L-tryptophan [news].
Source
Nature. 353(6344):490, 1991 Oct 10.
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