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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
---------------------------------------------------------------------------
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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