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gulf war syndrome


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gulf war syndrome

Persian Gulf Syndrome
Wallace, H. L., 2nd, B. Natelson, W. Gause, and J. Hay.
1999. Human herpesviruses in chronic fatigue syndrome. Clin Diagn Lab Immunol. 6(2):216-23.

We have conducted a double-blind study to assess the possible involvement of the human herpesviruses (HHVs) HHV6, HHV7, Epstein-Barr virus (EBV), and cytomegalovirus in chronic fatigue syndrome (CFS) patients compared to age-, race-, and gender-matched controls. The CFS patient population was composed of rigorously screened civilian and Persian Gulf War veterans meeting the Centers for Disease Control and Prevention's CFS case definition criteria. Healthy control civilian and veteran populations had no evidence of CFS or any other exclusionary medical or psychiatric condition. Patient peripheral blood mononuclear cells were analyzed by PCR for the presence of these HHVs. Using two- tailed Fisher's exact test analyses, we were unable to ascertain any statistically significant differences between the CFS patient and control populations in terms of the detection of one or more of these viruses. This observation was upheld when the CFS populations were further stratified with regard to the presence or absence of major axis I psychopathology and patient self-reported gradual versus acute onset of disease. In tandem, we performed serological analyses of serum anti- EBV and anti-HHV6 antibody titers and found no significant differences between the CFS and control patients.

BACKGROUND: Various symptoms in military personnel in the Persian Gulf War 1990-91 have caused international speculation and concern. We investigated UK servicemen. METHODS: We did a cross-sectional postal survey on a random sample of Gulf War veterans (Gulf War cohort, n=4248) and, stratified for age and rank, servicemen deployed to the Bosnia conflict (Bosnia cohort, n=4250) and those serving during the Gulf War but not deployed there (Era cohort, n=4246). We asked about deployment, exposures, symptoms, and illnesses. We analysed men only. Our outcome measures were physical health, functional capacity (SF-36), the general health questionnaire, the Centers for Disease Control and Prevention (CDC) multisymptom criteria for Gulf War illness, and post- traumatic stress reactions. FINDINGS: There were 8195 (65.1%) valid responses. The Gulf War cohort reported symptoms and disorders significantly more frequently than those in the Bosnia and Era cohorts, which were similar. Perception of physical health and ability were significantly worse in the Gulf War cohort than in the other cohorts, even after adjustment for confounders. Gulf War veterans were more likely than the Bosnia cohort to have substantial fatigue (odds ratio 2.2 [95% CI 1.9-2.6]), symptoms of post-traumatic stress (2.6 [1.9- 3.4]), and psychological distress (1.6 [1.4-1.8]), and were nearly twice as likely to reach the CDC case definition (2.5 [2.2-2.8]). In the Gulf War, Bosnia, and Era cohorts, respectively, 61.9%, 36.8%, and 36.4% met the CDC criteria, which fell to 25.3%, 11.8%, and 12.2% for severe symptoms. Potentially harmful exposures were reported most frequently by the Gulf War cohort. All exposures showed associations with all of the outcome measures in the three cohorts. Exposures specific to the Gulf were associated with all outcomes. Vaccination against biological warfare and multiple routine vaccinations were associated with the CDC multisymptom syndrome in the Gulf War cohort. INTERPRETATION: Service in the Gulf War was associated with various health problems over and above those associated with deployment to an unfamiliar hostile environment. Since associations of ill health with adverse events and exposures were found in all cohorts, however, they may not be unique and causally implicated in Gulf-War-related illness. A specific mechanism may link vaccination against biological warfare agents and later ill health, but the risks of illness must be considered against the protection of servicemen.

STUDY OBJECTIVES: To study the flow-volume loop for evidence of variable extrathoracic airflow obstruction in Persian Gulf War veterans. DESIGN: Retrospective case-control, single-center study. SETTING: The pulmonary division of an academic health-care center. SUBJECTS: A convenience sample of the Persian Gulf Registry. MEASUREMENTS AND INTERVENTIONS: (1) Midvital capacity ratio (ratio of maximum forced midexpiratory to maximum forced midinspiratory flow). This ratio is the criterion standard for the diagnosis of variable extrathoracic airflow obstruction. (2) Evaluation of the anatomy and function of the extrathoracic airway by fiberoptic bronchoscopy. (3) Further investigation into the airway abnormality by histologic evaluation of tracheal biopsy samples in Gulf War veterans only. RESULTS: Midvital capacity was > 1.0 in 32 of 37 Gulf War veterans compared with only 11 of 38 control subjects. The mean (+/-SD) value was 1.37+/-0.4 among Gulf War veterans and 0.88+/-0.3 among control subjects (p=0.0000005). FVC and its ratio to FEV1 were normal in all these subjects. Bronchoscopy showed inflamed larynx and trachea in all (n=17) Gulf War veterans. Histologic study showed chronic inflammation of the trachea in everyone (n=12) who had an adequate biopsy sample. CONCLUSION: Physicians should be made aware of the presence of chronic inflammation of the upper airways and inspiratory airflow limitation in a number of Gulf War veterans.

The purpose of this study was to evaluate immune function through the assessment of lymphocyte subpopulations (total T cells, major histocompatibility complex [MHC] I- and II-restricted T cells, B cells, NK cells, MHC II-restricted T-cell-derived naive and memory cells, and several MHC I-restricted T-cell activation markers) and the measurement of cytokine gene expression (interleukin 2 [IL-2], IL-4, IL-6, IL-10, IL-12, gamma interferon [IFN-gamma], and tumor necrosis factor alpha [TNF-alpha]) from peripheral blood lymphocytes. Subjects included two groups of patients meeting published case definitions for chronic fatigue syndrome (CFS)-a group of veterans who developed their illness following their return home from participating in the Gulf War and a group of nonveterans who developed the illness sporadically. Case control comparison groups were comprised of healthy Gulf War veterans and nonveterans, respectively. We found no significant difference for any of the immune variables in the nonveteran population. In contrast, veterans with CFS had significantly more total T cells and MHC II+ T cells and a significantly higher percentage of these lymphocyte subpopulations, as well as a significantly lower percentage of NK cells, than the respective controls. In addition, veterans with CFS had significantly higher levels of IL-2, IL-10, IFN-gamma, and TNF-alpha than the controls. These data do not support the hypothesis of immune dysfunction in the genesis of CFS for sporadic cases of CFS but do suggest that service in the Persian Gulf is associated with an altered immune status in veterans who returned with severe fatiguing illness.

OBJECTIVE: To review the clinical findings in the first 1000 veterans seen in the Ministry of Defence's Gulf war medical assessment programme to examine whether there was a particular illness related to service in the Gulf. DESIGN: Case series of 1000 veterans who presented to the programme between 11 October 1993 and 24 February 1997. SUBJECTS: Gulf war veterans. MAIN OUTCOME MEASURES: Diagnosis of veterans' conditions according to ICD-10 (international classification of diseases, 10th revision). Cases referred for psychiatric assessment were reviewed for available diagnostic information from consultant psychiatrists. RESULTS: 588 (59%) veterans had more than one diagnosed condition, 387 (39%) had at least one condition for which no firm somatic or psychological diagnosis could be given, and in 90 (9%) veterans no other main diagnosis was made. Conditions characterised by fatigue were found in 239 (24%) of patients. At least 190 (19%) patients had a psychiatric condition, which in over half was due to post-traumatic stress disorder. Musculoskeletal disorders and respiratory conditions were also found to be relatively common (in 182 (18%) and 155 (16%) patients respectively). CONCLUSION: Many Gulf war veterans had a wide variety of symptoms. This initial review shows no evidence of a single illness, psychological or physical, to explain the pattern of symptoms seen in veterans in the assessment programme. As the veterans assessed by the programme were all self selected, the prevalence of illness in Gulf war veterans cannot be determined from this study. Furthermore, it is not known whether the veterans in this study were representative of sick veterans as a group.

The purpose of this study was to determine if Gulf War veterans with complaints of severe fatigue and/or chemical sensitivity (n = 72) fulfill case definitions for chronic fatigue syndrome (CFS) and/or multiple chemical sensitivity (MCS) and to compare the characteristics of those veterans who received a diagnosis of CFS (n = 24) to a group of non-veterans diagnosed with CFS (n = 95). Thirty-three veterans received a diagnosis of CFS with 14 having MCS concurrently; an additional six had MCS but did not fulfill a case definition for CFS. The group of fatigued veterans receiving a diagnosis of CFS was comprised of significantly fewer women and fewer Caucasians than the civilian group, and significantly fewer veterans reported a sudden onset to their illness. Veterans with CFS had a milder form of the illness than their civilian counterparts based on medical examiner assessment of the severity of the symptoms, reported days of reduced activity, and ability to work. Since CFS in veterans seems less severe than that seen in civilians, the prognosis for recovery of veterans with this disorder may be better.

Stress due to forced swimming was recently shown to allow penetration of pyridostigmine (PYR) into the brain of mice. Accordingly, it was suggested that in troops exposed to emotional stress under conditions of war, as during the Gulf War, the BBB may have unexpectedly become permeable to PYR thus leading to an increased frequency of CNS symptoms. In this study, the entry of PYR into the brain was investigated in guinea pigs subjected to different heat stress levels. In a first group, guinea pigs were maintained at room temperature for 2 hours, their core temperature remaining stable at about 39.8 degrees C. In a second group, animals were placed in a climatic chamber in order to keep their core temperature at 41.5 degrees C for 2 hours. In a third group, animals were subjected to a high ambient temperature (42.6 degrees C) during about 2 hours and developed heatstroke symptoms, their core temperature progressively increasing and reaching around 44.3 degrees C. In each group, the stress of the animals was assessed by measuring the increase of plasma cortisol level. PYR (0.2 mg/kg, s.c.) was injected 90 minutes after beginning the experiment. Penetration of the drug into the brain was examined by measurement of acetylcholinesterase (AChE) activity in the cortex, the striatum and the hippocampus of the animals 30 minutes after PYR administration. A passage of this drug into the brain was also evaluated autoradiographically after i.v. injection of tritiated PYR 90 minutes after the beginning of the experiment (100 microCi/animal). Whatever the group examined, no entry of PYR into the CNS could be detected. Exposure to an ambient temperature at 42.6 degrees C for 2 hours resulted by itself in a partial inhibition of cerebral AChE activity. Our results, which agree with previous data obtained in humans exposed to heat stress, are opposite to the recent research showing a central passage of PYR in mice following a forced swim stress test. This demonstrated that the penetration of PYR into the brain of rodents under stress depends on the experimental conditions used (animal species, nature of the stressor, etc.). Extrapolations to humans of results primarily obtained in rodents about central passage of a drug under stress must thus be done very carefully.

Toxic or environmental exposures have been suggested as a possible cause of symptoms reported by Gulf War veterans. To further explore this hypothesis, we analyzed findings in 18,495 military personnel evaluated in the Department of Defense Comprehensive Clinical Evaluation Program. The program was established in 1994 to evaluate Persian Gulf veterans eligible for Department of Defense medical care who had health concerns after service in the Persian Gulf during Operation Desert Shield/Desert Storm. The evaluation included a structured clinical assessment, a physician-administered symptom checklist, and a patient questionnaire addressing self-reported exposures, combat experiences, and work loss. Among 18,495 patients examined, the most common symptoms were joint pain, fatigue, headache, memory or concentration difficulties, sleep disturbances, and rash. Symptom onset was often delayed, with two-thirds of symptoms not developing until after individuals returned from the Gulf War and 40% of symptoms having a latency period exceeding one year. There was no association between individual symptoms and patient demographics, specific self-reported exposures, or types of combat experience. Increased symptom counts were associated with work loss, the number of self-reported exposures, the number of types of combat experience, and certain ICD-9 diagnostic categories, particularly psychological disorders. Prolonged latency of symptom onset and the lack of association with any self-reported exposures makes illness related to toxic exposure less likely.

We studied whether regular, active-duty servicemen deployed to the Persian Gulf War were at increased risk of testicular cancer compared with nondeployed Gulf War-era servicemen from August 1991 through March 31, 1996, using a Cox proportional hazards model for survival analysis with covariates. Race was an important predictor of hospitalization for testicular cancer [rate ratio (RR) = 0.19; 95% confidence interval (CI) = 0.12-0.29 for blacks, and RR = 0.59; 95% CI = 0.39-0.91 for Hispanics, other, and unknown (combined), relative to whites]. Age effects were modest (RR = 1.19; 95% CI = 0.91-1.56 for those of ages 22- 25 years, and RR = 1.24; 95% CI = 0.96-1.59 for those of ages 26-31 years, compared with those of ages 17-21 years). Risk also varied with occupation (RR = 1.56; 95% CI = 1.23-2.00 for those in electronic equipment repair; RR = 1.26; 95% CI = 1.01-1.58 for those in electrical/mechanical repair; and RR = 1.42; 95% CI = 0.93-2.17 for those in construction-related trades, compared with those in other occupations). Deployment status was not important (RR = 1.05; 95% CI = 0.86-1.29 for the deployed compared with the nondeployed). There was an increase in testicular cancer in the deployed group in the immediate postwar period that was consistent with a previous report of a standardized RR of 2.12; 95% CI = 1.11-4.02 (compared with the nondeployed group) in the last 5 months of 1991, but by 4 years after the end of deployment, the cumulative risks for the two groups were not different. An additional analysis suggested that the immediate postwar increase in the deployed was likely due to regression to the mean after a healthy serviceman selection effect for deployment and the deferment of care during deployment.

While the lore of anticholinesterases (antiChEs), particularly physostigmine and its natural source, the Calabar bean, is a subject of ethnomedicine and predates our scientific era, the pharmacological development of physostigmine analogues and related agents and of the antiChEs of the organophosphorus (OP) type, is a matter of the last two centuries; this development has reached an exponential character in the last fifty years. This explosion relates to certain uses and misuses of these drugs and this aspect of antiChEs is the main focus of this article. Firstly, there is the matter of Senile Dementia of Alzheimer's Type (SDAT); while there are several clinical applications of antiChEs, their employment in the treatment of SDAT is the last and most intense foray in their medical history and this article will focus on the uses and misuses of antiChEs in this area. Secondly, the applied use of antiChEs as insecticides which coincided with the historical development of OP antiChEs was and is, of major significance for the agricultural economy of both advanced and underdeveloped countries, as this employment may mean the difference between life and starvation. However, there are notable dangers with this application of OP drugs, as will be emphasized in this article. Thirdly, there is the significant and tragic development of the OP drugs as warfare agents and tools for terrorists and rogue states and this article will discuss the several types of toxicity of OP agents and their mechanisms, the enigma of the Persian Gulf War Syndrome being particularly stressed. Altogether, the immense range of antiChE topics includes areas of great basic interest and of practical applications that are of significant benefit to mankind as well as of potential danger.

Since the end of the Gulf War, tens of thousands of American, Canadian and British soldiers who participated in that war have claimed to be suffering from a variety of incapacitating symptoms which are generally termed as Gulf War Syndrome (GWS). The symptoms are multiple but mainly consist of excessive tiredness, muscle and joint pain, loss of balance, sensory symptoms, neurobehavioural manifestations, diarrhoea, bladder dysfunction, sweating disturbances, and respiratory, gastrointestinal, musculoskeletal and skin manifestations. These veterans have been exposed to a variety of damaging or potentially damaging risk factors including environmental adversities, pesticides such as organophosphate chemicals, skin insect repellents, medical agents such as pyridostigmine bromide (NAPS), possible low-levels of chemical warfare agents, multiple vaccinations in combinations, depleted uranium, and other factors. A large number of basic research findings, clinical epidemiological studies, and case control studies are reviewed to try and link them together to produce a coherent picture and to demonstrate the complexity of the interaction of biological systems, environmental and genetic factors, combinations of drugs and toxins with human health. The findings of these studies so far have demonstrated that many of the previous assumptions made about the 'safety' of certain drugs and toxic substances or vaccines must be radically reviewed. Many of the findings have far reaching implications not only in terms of explanation of what might have gone wrong during the Gulf War, but also have wider implications for many occupational groups who are exposed daily to some of these risk factors. More open-mindedness and much less prejudice are required concerning the basic biology of interactions of the above factors and their effects on cell functions and wider intelligent research is urgently required with high priority. This review highlights the importance of intelligent research for answers for a new phenomenon, and demonstrates the necessity for a combination of this approach with high quality epidemiological research. The reader will notice an emerging clear picture that the majority (if not all) of these advances have been achieved from studies funded by independent or charity organizations rather than by the responsible authorities who are supposed and are duty bound to take on this task.

Since the Persian Gulf War ended in 1991, many veterans have sought medical evaluation in the Department of Veterans Affairs Persian Gulf Veterans' Health Registry (VA registry) or the Department of Defense's Comprehensive Clinical Evaluation Program (DoD registry). Using combined data collected from 1993 to 1997 from the VA and DoD registries, the authors compared the characteristics of registry participants (n=74,653) with those of all Gulf War veterans (n=696,531) to determine the personnel most likely to seek medical evaluation. Using multiple logistic regression, the authors found that service branch and type were strongly associated with registry participation, with Army (adjusted odds ratio (OR 4.7, 95% confidence interval (CI) 4.6-4.9) and National Guard (OR=2.6, 95% CI 2.5-2.6) personnel at highest odds compared with reference category personnel. Registry participants also were more likely to have been stationed in the Gulf War theater during the fighting (OR=2.2), to be older (>31 years/22 years OR=2.1), to have been an enlisted person (OR=2.0), to have been construction workers (OR=1.3), to be female (OR=1.3), and to have been hospitalized during the 12-month period before the war (OR=1.2). These findings are useful in generating hypotheses regarding postwar morbidity. They also suggest that subpopulations of Gulf War veterans have a higher prevalence of symptoms and merit further study.

CONTEXT: Gulf War (GW) veterans report nonspecific symptoms significantly more often than their nondeployed peers. However, no specific disorder has been identified, and the etiologic basis and clinical significance of their symptoms remain unclear. OBJECTIVES: To organize symptoms reported by US Air Force GW veterans into a case definition, to characterize clinical features, and to evaluate risk factors. DESIGN: Cross-sectional population survey of individual characteristics and symptoms and clinical evaluation (including a structured interview, the Medical Outcomes Study Short Form 36, psychiatric screening, physical examination, clinical laboratory tests, and serologic assays for antibodies against viruses, rickettsia, parasites, and bacteria) conducted in 1995. PARTICIPANTS AND SETTING: The cross-sectional questionnaire survey included 3723 currently active volunteers, irrespective of health status or GW participation, from 4 air force populations.The cross-sectional clinical evaluation included 158 GW veterans from one unit, irrespective of health status. MAIN OUTCOME MEASURES: Symptom-based case definition; case prevalence rate for GW veterans and nondeployed personnel; clinical and laboratory findings among veterans who met the case definition. RESULTS: We defined a case as having 1 or more chronic symptoms from at least 2 of 3 categories (fatigue, mood-cognition, and musculoskeletal). The prevalence of mild-to-moderate and severe cases was 39% and 6%, respectively, among 1155 GW veterans compared with 14% and 0.7% among 2520 nondeployed personnel. Illness was not associated with time or place of deployment or with duties during the war. Fifty-nine clinically evaluated GW veterans (37%) were noncases, 86 (54%) mild-to- moderate cases, and 13 (8%) severe cases. Although no physical examination, laboratory, or serologic findings identified cases, veterans who met the case definition had significantly diminished functioning and well-being. CONCLUSIONS: Among currently active members of 4 Air Force populations, a chronic multisymptom condition was significantly associated with deployment to the GW. The condition was not associated with specific GW exposures and also affected nondeployed personnel.

OBJECTIVE: Pain in the joints and other areas has been a frequent complaint among veterans of Operation Desert Storm who are experiencing unexplained illness. We characterized the rheumatic manifestations of a group of veterans of the Persian Gulf War who were referred to a rheumatology clinic. METHODS: Consecutive South Texas veterans of the Persian Gulf War who were referred for evaluation of rheumatic manifestations underwent a comprehensive evaluation of their musculoskeletal symptoms, pain, and health related quality of life. RESULTS: Of 928 veterans evaluated in a screening clinic for unexplained symptoms, 145 had rheumatic manifestations (15.6%) and were referred to a rheumatology clinic. The most common diagnosis was fibromyalgia, present in 49 patients (33.8%), followed by various soft tissue problems in 25 (17.2%), nonspecific arthralgias in 14 (9.6%), and clinical or radiographic osteoarthritis in 16 (11.0%). In 39 patients (26.9%), no symptoms were present at the time of the evaluation, a careful musculoskeletal examination and laboratory tests were normal, and no diagnosis was possible. Two patients had Reiter's syndrome. Four had a positive rheumatoid factor and 3 had antinuclear antibodies, but none of these had clinical evidence of rheumatoid arthritis or systemic lupus erythematosus. Pain was present in nearly all patients and was widely distributed, with no body area spared in this group of patients. The most frequent painful areas were the knees in > 65%, the lower back in > 60%, the shoulders in 50%, and the hands and wrists in 35%. Widespread body pain was present in 65.1% of the veterans. Average values of all 8 scales measured by the SF-36 health survey were below the 25th percentile of published national norms, with pain and the number of nonarticular rheumatic symptoms explaining most of the decreased health related quality of life in the veterans we evaluated. CONCLUSION: No specific rheumatic diagnosis is characteristic of Gulf War veterans with unexplained illness referred to a rheumatology clinic. However, pain is common and widespread in these patients, and their health related quality of life is poor. Further research is necessary to determine the cause of the symptoms of veterans of the Gulf War.

Research suggests that individuals commonly describe persistent symptoms or syndromes after a war. After the Persian Gulf War, the Department of Veterans Affairs and the Department of Defense initiated registries and expedited health care for those with Gulf War-related health concerns. At Walter Reed Army Medical Center, the Gulf War Health Center was created in mid-1994 to contribute a continuum of care for those with Gulf War-related health problems. The purpose of this report is to describe the Gulf War Health Center's Specialized Care Program, a 3-week intensive outpatient multidisciplinary treatment program for people with persistent, disabling Gulf War-related symptoms. The program uses an evidence-based model of multidisciplinary care employed at chronic pain centers internationally and shown to yield stable improvements in pain, mood, health care use, and return to work rates. A patient is described to illustrate how the program works. Finally, a Deployment Medicine Treatment Center is proposed, a multidisciplinary treatment center like the Specialized Care Program that would offer care to those with persistent, disabling symptoms after all future deployments.

To investigate complaints of Gulf War veterans, epidemiologic, case- control and animal modeling studies were performed. Looking for OPIDP variants, our epidemiologic project studied 249 Naval Reserve construction battalion (CB24) men. Extensive surveys were drawn for symptoms and exposures. An existing test (PAI) was used for neuropsychologic. Using FACTOR, LOGISTIC and FREQ in 6.07 SAS, symptom clusters were sought with high eigenvalues from orthogonally rotated two-stage factor analysis. After factor loadings and Kaiser measure for sampling adequacy (0.82), three major and three minor symptom clusters were identified. Internally consistent by Cronbach's coefficient, these were labeled syndromes: (1) impaired cognition; (2) confusion-ataxia; (3) arthro-myo-neuropathy; (4) phobia-apraxia; (5) fever-adenopathy; and (6) weakness-incontinence. Syndrome variants identified 63 patients (63/249, 25%) with 91 syndromes. With pyridostigmine bromide as the drug in these drug-chemical exposures, syndrome chemicals were: (1) pesticide-containing flea and tick collars (P 0.001); (2) alarms from chemical weapons attacks (P 0.001), being in a sector later found to have nerve agent exposure (P 0.04); and (3) insect repellent (DEET) (P 0.001). From CB24, 23 cases, 10 deployed and 10 non-deployed controls were studied. Auditory evoked potentials showed dysfunction (P 0.02), nystagmic velocity on rotation testing, asymmetry on saccadic velocity (P 0.04), somatosensory evoked potentials both sides (right P 0.03, left P 0.005) and synstagmic velocity after caloric stimulation bilaterally (P-range, 0.02-0.04). Brain dysfunction was shown on the Halstead Impairment Index (P 0.01), General Neuropsychological Deficit Scale (P 0.03) and Trail Making part B (P 0.03). Butylcholinesterase phenotypes did not trend for inherent abnormalities. Parallel hen studies at Duke University established similar drug-chemical delayed neurotoxicity. These investigations lend credibility that sublethal exposures to drug-chemical combinations caused delayed-onset neurotoxic variants.

'Persian Gulf syndrome' refers to a group of clinical findings found in military personnel who served in the Persian Gulf War. The most commonly reported symptoms include chronic fatigue, headache, and neurologic disorders. Recently, new information has linked Whipple's disease and Ki-1 anaplastic large cell lymphoma to this syndrome. Presented here is an unusual case of multiple giant cell tumors of the hand in a patient with documented Persian Gulf syndrome. The epidemiologic significance between these two entities is unclear, because this is a single reported case. However, the practical message is clear. Physicians must meticulously evaluate patients who are veterans of the Persian Gulf conflict to further our understanding and confirm the existence of this syndrome.

Interpretation of symptom-limited exercise testing requires analysis of a large body of simultaneously recorded cardiopulmonary data. Karlman Wasserman has recommended an algorithmic approach to interpretation (WA) that leads to a dichotomous choice between pulmonary and cardiovascular impairment. An alternative algorithm published by William Eschenbacher (EA) provides for concurrent assessment of cardiovascular and pulmonary exercise impairment. We analyzed a group of 29 individuals referred to the Pulmonary Physiology Laboratory at the Washington Veterans Affairs Medical Center for evaluation of dyspnea following service in the Persian Gulf War to assess the concordance of the two algorithms in determining the cause of dyspnea and exercise impairment in these individuals. They each performed a progressive, ramped, symptom-limited exercise test on a bike for a minimum of 6 min. Exercise measurements were analyzed by both interpretive algorithms. Concordance was found in 28% of tests. The greatest discordance occurred in identifying pulmonary limitation. Eleven had pulmonary limitation by EA; of these, WA found 1 to have pulmonary limitation, 5 to be normal, 4 indeterminate, and 1 musculoskeletal limitation. Of the 11 with pulmonary limitation by EA, but not by WA, 5 had abnormal resting pulmonary function measurements. Analysis of the differences between these two interpretive approaches is given. The EA algorithm may be more sensitive for detecting exercise impairment of pulmonary origin, but its specificity remains to be determined.

This cross-sectional telephone survey study assessed prevalence rates of current chemical sensitivity, frequency of chemical odor intolerance, and self-reported Persian Gulf chemical exposures among 41 randomly sampled Department of Veterans Affairs outpatients who were Persian Gulf War (PGW) and PGW-era veterans. The participants were drawn from an initial random list of 100 veterans, of whom 28 PGW and 20 era veterans had correct telephone data on file. Of those contacted, 86% of PGW veterans (24/28) and 85% of era veterans (17/20) agreed to participate. Significantly more PGW veterans with poorer global health after military service reported considering themselves now 'especially sensitive to certain chemicals' (86%, 12/14) than did the PGW veterans or era veterans in stable health (both comparison groups 30%, 3/10). Among PGW veterans, the subset with worse health associated with marked increases in chemical odor intolerance since their military service had a significantly higher odds ratio for exposure to multiple chemicals, notably wartime pesticides and insect repellent, than did comparison groups. The high rate of chemical sensitivity of PGW veterans with deteriorated health is almost three times that in PGW-era veterans and in elderly primary care outpatient veterans at the same Department of Veterans Affairs medical center and in community-based civilian samples (i.e., 30%). These preliminary findings suggest the need for further study of chemical sensitivity, including tests for acquired increases in neural sensitizability to multiple low-level chemicals, in ill PGW veterans.

The symptom of intolerance to low levels of environmental chemicals (CI, chemical intolerance) is a feature of several controversial polysymptomatic conditions that overlap symptomatically with depression and somatization, i.e., chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivity, and Persian Gulf syndrome. These syndromes can involve many somatic symptoms consistent with possible inflammation. Immunological or neurogenic triggering might account for such inflammation. Serum neopterin, which has an inverse relationship with l-tryptophan availability, may offer a marker of inflammation and macrophage/monocyte activation. This study compared middle-aged women with CI (who had high levels of affective distress; n = 14), depressives without CI (n = 10), and normals (n = 11). Groups did not differ in 4 p.m. resting levels of serum neopterin. However, the CI alone had strong positive correlations between neopterin and all of the scales measuring somatization. These preliminary findings suggest the need for additional research on biological correlates of 'unexplained' multiple somatic symptoms in subtypes of apparent somatizing disorders.

Chemical sensitivity Syndromes refers to aggregations of symptoms marked by largely subjective neurobehavioral complaints and hypothesized links to immune system dysfunction. The entities reviewed here consist of the Multiple Chemical Sensitivity Syndrome, the Sick Building Syndrome, the Chronic Fatigue Syndrome, and the Gulf War Syndrome. Except for the Chronic Fatigue Syndrome, toxic chemical exposures are accorded a significant role in their etiology. The connections are ambiguous because of the variety of chemical agents cited and, for the most part, the relatively low levels at which exposures occur. Conventional clinical signs are also typically lacking. Explanatory mechanisms include psychiatric diagnoses such as somatization, behavioral mechanisms such as conditioning and generalization, neuropharmacological mechanisms such as sensitization, and psychoneuroimmunological mechanisms such as those involving the hypothalamic-pituitary-adrenal axis. Laboratory animal experimentation and controlled clinical trials, especially with inhaled material, provide the means for exploring the proffered explanations.

Troops in the Persian Gulf War have registered complaints consistent with CNS dysfunction that emerged after returning from the Gulf. A common experience among Persian Gulf War veterans was exposure to pyridostigmine bromide (PB) for prophylaxis against nerve gas exposure. To determine whether PB causes emergent CNS dysfunction, Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats were given PB for 7 consecutive days in their drinking water. The WKY, but not the SD, rats exhibited a delayed-onset, persistently exaggerated startle response. The WKY rats exhibited exaggerated startle responses that appeared 15 days after the end of PB treatment and were still evident 22 days after the end of treatment. Both the duration and the magnitude of the exaggerated startle responses were related to the dosage of PB. The PB-treated rats exhibited normal short-term and long-term habituation. However, exaggerated startle responses were related to the development of enhanced short-term sensitization. Treating the rats for a second time, 7 weeks after the end of the first PB treatment, induced an exaggerated startle response that appeared sooner and dissipated faster than was evident after the first PB treatment. Inasmuch as the WKY rat has inherently low butyrylcholinesterase activity, a scavenger for PB, these results suggest that prophylactic PB may influence CNS function in individuals with low butyrylcholinesterase activity. Elaboration of the factors that mediate enhanced sensitization in the WKY rat may provide insight into some of the complaints registered by veterans of the Persian Gulf War.

The exposure of two Iranian victims of the Iran-Iraq conflict (1980- 1988) to sulfur mustard was established by immunochemical and mass spectrometric analysis of blood samples taken 22 and 26 days after alleged exposure. One victim suffered from skin injuries compatible with sulfur mustard intoxication but did not have lung injuries; the symptoms of the other victim were only vaguely compatible with sulfur mustard intoxication. Both patients recovered. Immunochemical analysis was based on detection of the N7-guanine adduct of the agent in DNA from lymphocytes and granulocytes, whereas the N-terminal valine adduct in globin was determined by gas chromatography-mass spectrometry after a modified Edman degradation. The valine adduct levels correspond with those found in human blood after in vitro treatment with 0.9 microM sulfur mustard.

Simultaneous exposure to DEET and permethrin was recently proposed to be associated with the 'Gulf War Syndrome.' However, no studies have reported the percutaneous absorption of DEET and permethrin when applied simultaneously to the skin as a mixture, the relevant route of exposure in the Persian Gulf. The present study quantitates percutaneous absorption of DEET and permethrin after coadministration to rodent and pig skin in vitro. Dosing solutions were also prepared with either acetone, dimethyl sulfoxide (DMSO), or ethanol to compare vehicle effects on percutaneous absorption of permethrin and DEET. The influence of DEET on carbaryl absorption and dermal disposition was also assessed in pig studies to statistically demonstrate DEET effects in acetone or DMSO and different solvent concentrations. Topical application of permethrin + DEET resulted in absorption of DEET (1-20% dose), but no permethrin. Permethrin (1.2-1.7% dose) was detected only when mouse skin was dosed solely with permethrin, a finding suggesting that DEET decreased permethrin absorption. DEET also inhibited carbaryl absorption in acetone mixtures, but had no effect on DMSO mixtures. Irrespective of solvent, DEET did not enhance carbaryl penetration into skin. For DEET, absorption was greater in mouse skin (10.7-20.6% dose) than in rat skin (1.1-5.2% dose) and pig skin (2.8% dose). The extent of DEET absorption was greater with DMSO and acetone than with ethanol in rat and mouse skin. These studies support DEET, but not permethrin or carbaryl, as having sufficient systemic exposure to potentially cause signs of toxicity when simultaneously applied with pesticides. Furthermore, these studies demonstrated that DEET does not necessarily enhance dermal absorption of all toxicants as was originally hypothesized.

In response to ongoing complaints of memory, attention, and problem- solving difficulties among veterans of Operation Desert Storm and Shield (ODSS), a sample of 44 male veterans of ODSS underwent a comprehensive neuropsychological evaluation. Deficits relative to normative data were observed only on finger dexterity (Grooved Pegboard, bilaterally) and the Stroop Color and Word Test. Those with impaired Pegboard performance had lower performance on other tasks requiring psychomotor speed. Those with impaired Stroop had significantly lower motor and set-shifting performance. Scores of both impaired groups were higher on many clinical and supplemental scales of the MMPI. Despite subjective cognitive complaints reported in 39% of the overall sample, veterans with cognitive complaints differed from their peers primarily in greater psychological distress as depicted on the MMPI. The data are presented as preliminary clinical findings.

OBJECTIVE: To comprehensively evaluate complaints of muscle fatigue, weakness, and myalgias in Persian Gulf veterans (PGV). BACKGROUND: Approximately 700,000 American troops were deployed to the Persian Gulf during Desert Shield and Desert Storm. Upon return from the Gulf, some PGV developed unexplained illnesses, and special referral centers were established for the evaluation of these patients. Among the most common symptoms of these PGV are fatigue, weakness, and myalgias. An Institute of Medicine committee recommended further exploration into the possible etiologies of these complaints. METHODS: Twenty PGV with severe muscle fatigue, weakness, or myalgias that interfered with their daily activities were referred for an extensive prospective neuromuscular evaluation. Routine laboratory studies included serum creatine kinase (CK), erythrocyte sedimentation rate, thyroid function tests, and exercise forearm tests. All patients received nerve conduction studies (NCS), repetitive nerve stimulation, quantitative and single-fiber electromyography (EMG), and muscle biopsies. RESULTS: Manual muscle strength examinations were normal in all patients. Six patients had mildly elevated CKs (range 223 to 768 IU/l); otherwise, laboratory tests were unremarkable. NCS were normal except in 2 patients with carpal tunnel syndrome. Quantitative EMGs were normal. One patient had mildly increased jitter on single-fiber EMG. Muscle biopsies demonstrated minor nonspecific abnormalities in 5 patients (i.e., increased central nuclei, rare necrotic fibers, tubular aggregates). CONCLUSIONS: Despite severe subjective symptoms, most of our patients had no objective evidence of neuromuscular disease. Mildly increased CKs or nonspecific histologic abnormalities on muscle biopsy were evident in 8 patients but were not believed to be clinically significant in most. We found no evidence of a specific neuromuscular disorder in any patient. Exposures to toxins during the Persian Gulf War were not likely responsible for our patients' symptoms.

OBJECTIVE: To assess the prevalence of self-reported symptoms and illnesses among military personnel deployed during the Persian Gulf War (PGW) and to compare the prevalence of these conditions with the prevalence among military personnel on active duty at the same time, but not deployed to the Persian Gulf (non-PGW). DESIGN: Cross-sectional telephone interview survey of PGW and non-PGW military personnel. The study instrument consisted of validated questions, validated questionnaires, and investigator-derived questions designed to assess relevant medical and psychiatric conditions. SETTING: Population-based sample of military personnel from Iowa. STUDY PARTICIPANTS: A total of 4886 study subjects were randomly selected from 1 of 4 study domains (PGW regular military, PGW National Guard/Reserve, non-PGW regular military, and non-PGW National Guard/Reserve), stratifying for age, sex, race, rank, and branch of military service. MAIN OUTCOME MEASURES: Self-reported symptoms and symptoms of medical illnesses and psychiatric conditions. RESULTS: Overall, 3695 eligible study subjects (76%) and 91% of the located subjects completed the telephone interview. Compared with non-PGW military personnel, PGW military personnel reported a significantly higher prevalence of symptoms of depression (17.0% vs 10.9%; Cochran-Mantel-Haenszel test statistic, P.001), posttraumatic stress disorder (PTSD) (1.9% vs 0.8%, P=.007), chronic fatigue (1.3% vs 0.3%, P.001), cognitive dysfunction (18.7% vs 7.6%, P.001), bronchitis (3.7% vs 2.7%, P.001), asthma (7.2% vs 4.1%, P=.004), fibromyalgia (19.2% vs 9.6%, P.001), alcohol abuse (17.4% vs 12.6%, P=.02), anxiety (4.0% vs 1.8%, P.001), and sexual discomfort (respondent, 1.5% vs 1.1%, P=.009; respondent's female partner, 5.1% vs 2.4%, P.001). Assessment of health-related quality of life demonstrated diminished mental and physical functioning scores for PGW military personnel. In almost all cases, larger differences between PGW and non-PGW military personnel were observed in the National Guard/Reserve comparison. Within the PGW military study population, compared with veterans in the regular military, veterans in the National Guard/Reserve only reported more symptoms of chronic fatigue (2.9% vs 1.0%, P=.03) and alcohol abuse (19.4% vs 17.0%, P=.004). CONCLUSIONS: Military personnel who participated in the PGW have a higher self-reported prevalence of medical and psychiatric conditions than contemporary military personnel who were not deployed to the Persian Gulf. These findings establish the need to further investigate the potential etiologic, clinical, pathogenic, and public health implications of the increased prevalence of multiple medical and psychiatric conditions in populations of military personnel deployed to the Persian Gulf.

The symptoms of Gulf War syndrome are compatible with the hypothesis that the immune system of affected individuals is biased towards a Th2- cytokine pattern. Factors that could lead to a Th2 shift among Gulf War veterans include exposure to multiple Th2-inducing vaccinations under stressful circumstances and the way in which such vaccinations were administered, which would be expected to maximise Th2 immunogenicity. These factors may have led to a long-term systemic shift towards a Th2- cytokine balance and to mood changes related to the immunoendocrine state. Other vaccines that lead to similar long-term, non-specific shifts in cytokine balance are well-established. If our hypothesis is proven, treatment may be possible with regimens that induce a systemic Th1 bias.

This article examines the potential relationship between Al Eskan disease and the Persian Gulf syndrome. Al Eskan disease, reported in Military Medicine in 1992, is a novel and previously unreported condition triggered by the exceptionally fine sand dust of the Central and Eastern Saudi Arabian peninsula. We repeat our study of the pathogenesis of Al Eskan disease to include the ultrastructural and microanalytical study of the sand, aerobiological studies of the Kingdom of Saudi Arabia, and the etiology, symptoms, and prevalence of the disease. We conclude that immunodepression resulting from the continued presence of sand particles less than 1 micron in diameter in the lungs and bodies of Persian Gulf veterans explains not only the symptoms of the hyperegic lung condition of phase I and the symptoms of phase II of Al Eskan disease, but also provides an important clue to a common factor in most cases of Persian Gulf illnesses. We include a discussion of most of the commonly suspected agents in the Persian Gulf syndrome. In this case, we conclude that each of these factors, such as oil well fires, old-world diseases, or depleted uranium, are probably adjuvant or contributing causes. The only common exposure that would lead to recognition of the Persian Gulf syndrome as a single medical condition, rather than a catch-all phrase for unrelated conditions, appears to be exposure to the ubiquitous, fine sand of the area, and a resulting immunosuppression that is aggravated by opportunistic infections and other nonmicrobial ailments.

A pilot study was undertaken to determine the occurrence and distribution of pathogenic nocardiae in Kuwaiti soil. A total of 102 soil samples collected from two localities were investigated by the paraffin bait technique. Nocardia asteroides was the only species isolated from 42 (41%) soil samples. None of the isolates fulfilled the criteria required for identification of N. farcinica or N. nova. Thirty one (73.8%) isolates showed equivalent growth at 45 degrees C and 35 degrees C, 17 (40.4%) isolates utilized acetamide for carbon and nitrogen requirements and 3 (7.1%) isolates showed delayed arylsulphatase activity. Only a solitary isolate was resistant to cefamandole. Soil samples originating from the Kuwait University Campus, Shuwaikh, which were rich in humus/organic matter, were more productive for N. asteroides (67%) than the samples which were devoid of it but were mixed with crude oil (39%). Sand samples that lacked organic matter and crude oil samples were least productive of N. asteroides. These preliminary findings do not suggest that massive oil contamination of soil in the Ahmadi oil field area during the Gulf war promoted the natural occurrence of N. asteroides. However, isolation of N. asteroides in as many as 41% of the soil sample is a significant observation warranting further epidemiologic studies including its possible role in the operation desert storm sickness syndrome. This is the first report on the natural occurrence of N. asteroides in Kuwait.
The prevalence of sleep apnea-hypopnea syndrome (SAHS) was investigated in a selected group of veterans of the Persian Gulf War at Brooke Army Medical Center. One hundred ninety-two self-referred patients participated in the full evaluation of the Comprehensive Clinical Evaluation Program (CCEP) for veterans of the Persian Gulf War. After completing an initial survey, an interview and examination were performed by staff internists. Forty-six participants with histories suggestive of a sleep disorder were referred for further evaluation. Those patients suspected of SAHS then completed a sleep disorders questionnaire and underwent standard nocturnal polysomnography (PSG). SAHS was defined as a respiratory disturbance index > or = 15 in a symptomatic patient. Fifteen of 46 patients undergoing PSG at this institution met criteria for SAHS. The majority of these patients had symptoms of fatigue and memory loss. Overall, 16 of the 192 patients (8.3%) in the CCEP of our institution were diagnosed with SAHS. SAHS may play a significant role in the symptom complex presented by many veterans of the Persian Gulf War.

Eighty-two Persian Gulf War veterans seen in clinic were referred for neuropsychological evaluation. Relatedness of neuropsychological and neurological functioning to subjective complaint, exposure, a clinical signs index, and possible interference variables was examined in a subsample of 49 who completed assessment. The subsample was representative of the entire group with respect to symptom severity. Variables representing sustained attention, grip strength, motor coordination, vibratory sense, finger-tip number writing perception, executive functioning, memory functioning, and subjective complaint were considered. Neuropsychological performance appeared to be more related to emotional functioning than demographic variables or variables associated with the war. Individual differences may be contributing to different emotional reactions to illnesses, perceptions of exposure risks and cognitive functioning, and responses to stress.

OBJECTIVE: To search for syndromes in Persian Gulf War veterans. PARTICIPANTS: Two hundred forty-nine (41%) of the 606 Gulf War veterans of the Twenty-fourth Reserve Naval Mobile Construction Battalion living in 5 southeastern states participated; 145 (58%) had retired from service, and the rest were still serving in the battalion. DESIGN: Participants completed a standardized survey booklet measuring the anatomical distributions or characteristics of each symptom, a booklet measuring wartime exposures, and a standard psychological personality assessment inventory. Two-stage factor analysis was used to disentangle ambiguous symptoms and identify syndromes. MAIN OUTCOME MEASURES: Factor analysis-derived syndromes. RESULTS: Of 249 participants, 175 (70%) reported having had serious health problems that most attributed to the war, and 74 (30%) reported no serious health problems. Principal factor analysis yielded 6 syndrome factors, explaining 71% of the variance. Dichotomized syndrome indicators identified the syndromes in 63 veterans (25%). Syndromes 1 ('impaired cognition,' characterized by problems with attention, memory, and reasoning, as well as insomnia, depression, daytime sleepiness, and headaches), 2 ('confusion-ataxia,' characterized by problems with thinking, disorientation, balance disturbances, vertigo, and impotence), and 3 ('arthro-myo-neuropathy,' characterized by joint and muscle pains, muscle fatigue, difficulty lifting, and extremity paresthesias) represented strongly clustered symptoms; whereas, syndromes 4 ('phobia-apraxia'), 5 ('fever- adenopathy'), and 6 ('weakness-incontinence') involved weaker clustering and mostly overlapped syndromes 2 and 3. Veterans with syndrome 2 were 12.5 times (95% confidence interval, 3.5-44.8) more likely to be unemployed than those with no health problems. A psychological profile, found in 48.4% of those with the syndromes, differed from posttraumatic stress disorder, depression, somatoform disorder, and malingering. CONCLUSION: These findings support the hypothesis that clusters of symptoms of many Gulf War veterans represent discrete factor analysis-derived syndromes that appear to reflect a spectrum of neurologic injury involving the central, peripheral, and autonomic nervous systems.

OBJECTIVE: To identify risk factors of factor analysis-derived Gulf War- related syndromes. DESIGN: A cross-sectional survey. PARTICIPANTS: A total of 249 Gulf War veterans from the Twenty-fourth Reserve Naval Mobile Construction Battalion. DATA COLLECTION: Participants completed standardized booklets measuring self-reported wartime exposures and present symptoms. MAIN OUTCOME MEASURES: Associations of factor analysis-derived syndromes with risk factors for chemical interactions that inhibit butyrylcholinesterase and neuropathy target esterase. RESULTS: Risk of syndrome 1 ('impaired cognition') was greater in veterans who reported wearing flea collars during the war (5 of 20, 25%) than in those who never wore them (7 of 229, 3%; relative risk [RR], 8.7; 95% confidence interval [CI], 3.0-24.7; P.001). Risk of syndrome 2 ('confusion-ataxia') increased with a scale of advanced adverse effects from pyridostigmine bromide (chi2 for trend, P.001), was greater among veterans who believed they had been involved in chemical weapons exposure (18 of 108, 17%) than in those who did not (3 of 141, 2%; RR, 7.8; 95% CI, 2.3-25.9; P.001), and was increased in veterans who had been in a sector of far northeastern Saudi Arabia on the fourth day of the air war (6 of 21, 29%) than in those who had not been (15 of 228, 7%; RR, 4.3; 95% CI, 1.9-10.0; P=.004). Effects of perceived chemical weapons exposure and advanced adverse effects from pyridostigmine were synergistic (Rothman S, 5.3; 95% CI, 1.04-26.7). Risk of syndrome 3 ('arthro-myo-neuropathy') increased with an index of frequency and amount of government-issued insect repellent containing 75% DEET (N,N-diethyl-m-toluamide) in ethanol applied during the war (chi2 for trend, P.001) and with advanced adverse effects from pyridostigmine (chi2 for trend, P.001). CONCLUSION: Some Gulf War veterans may have delayed, chronic neurotoxic syndromes from wartime exposure to combinations of chemicals that inhibit butyrylcholinesterase and neuropathy target esterase.

OBJECTIVE: To determine whether Gulf War-related illnesses are associated with central or peripheral nervous system dysfunction. DESIGN: Nested case-control study. PARTICIPANTS: Twenty-three veterans with factor analysis-derived syndromes (the cases), 10 well veterans deployed to the Gulf War (the deployed controls), and 10 well veterans not deployed to the Gulf War (the nondeployed controls). METHOD: With investigators blinded to group identities, participants underwent objective neurophysiological, audiovestibular, neuroradiological, neuropsychological, and blood tests. MAIN OUTCOME MEASURES: Evidence of neurologic dysfunction. RESULTS: Compared with the 20 controls, the 23 cases had significantly more neuropsychological evidence of brain dysfunction on the Halstead Impairment Index (P=.01), greater interside asymmetry of the wave I to wave III interpeak latency of brain stem auditory evoked potentials (P=.02), greater interocular asymmetry of nystagmic velocity on rotational testing, increased asymmetry of saccadic velocity (P=.04), more prolonged interpeak latency of the lumbar-to-cerebral peaks on posterior tibial somatosensory evoked potentials (on right side, P=.03, and on the left side, P=.005), and diminished nystagmic velocity after caloric stimulation bilaterally (P values range from .02 to .04). Cases (n=5) with syndrome 1 ('impaired cognition') were the most impaired on brain stem auditory evoked potentials (P=.005); those (n=13) with syndrome 2 ('confusion-ataxia') were the most impaired on the Halstead Impairment Index (P=.006), rotational testing (P=.01), asymmetry of saccadic velocity (P=.03), and somatosensory evoked potentials (P or =.01); and those (n=5) with syndrome 3 ('arthro-myo-neuropathy') were the most impaired on caloric stimulation (P or =.01). CONCLUSIONS: The 3 factor-derived syndromes identified among Gulf War veterans appear to represent variants of a generalized injury to the nervous system.

Medical policy-makers have concluded that stress from wartime trauma and deployment constitutes an important cause of the chronic physical symptoms observed in US veterans who served in the Persian Gulf War. The author reviewed scientific articles from peer-reviewed journals referenced in the final report of the Presidential Advisory Committee on Gulf War Veterans' illnesses and conducted a MEDLINE literature search. All reported prevalence rates of post-traumatic stress disorder (PTSD) in Gulf War veterans were defined by critical cutpoints on psychometric scales constructed by summing veterans' responses on standardized symptom questionnaires rather than by clinical psychiatric interviews. Observed PTSD rates varied from 0% to 36% (mean, 9%). Correcting for measurement errors with previously determined values of the sensitivity (range 0.77 to 0.96) and specificity (range 0.62 to 0.89) of the psychometric tests yielded estimated true PTSD rates of 0% for 18 of the 20 reported rates. Mean scores on the Mississippi PTSD scale in all subgroups of Gulf War veterans were within the range of values for well-adjusted Vietnam veterans (50-89) and far below that of Vietnam veterans with psychiatrically confirmed PTSD (120-140). Most PTSD and 'stress-related symptoms' reported in studies of Gulf War veterans appear to represent false-positive errors of measurement reflecting nonspecific symptoms of other conditions.

The purpose of the New Jersey Center for Environmental Hazards Research is to define the illness referred to as Persian Gulf Syndrome (PGS). Our preliminary data indicated that more than half of the Persian Gulf Registry (PGR) veterans reported illness characterized by severe fatigue and symptoms consistent with chemical sensitivities. Therefore, our research approach focuses on investigations of veterans with chronic fatigue syndrome (CFS) and multiple chemical sensitivities (MCS). Project 1 is an epidemiological study of 2800 PGR veterans. Symptoms, indices of Chronic Fatigue (CF) and Chemical Sensitivity (CS), and risk factors will be surveyed with mailed questionnaires. Risk factors include demographics, past medical history, psychosocial variables, Gulf War experiences such as prophylactic medication use, occupational and environmental exposures, and pesticide exposures. Symptoms will be clustered to define Gulf War Syndromes. Significant associations between risk factors and these symptom clusters will also be investigated Subjects identified as CF, CS, or both will be recruited into Projects 2 and 3. In Project 2, healthy veterans will be compared to veterans with CF, CS, and CF concurrent with CS. Veterans will undergo four studies: (1) viral-immunological, (2) psychiatric, psychological, behavioral, and neuropsychological, (3) autonomic dysregulation, and (4) marker of P4501A2 induction resulting from exposure to combusting material. The purpose of Project 3 is to test the autonomic, immunologic, neuropsychologic, and psychologic responses of veterans with CS or CF to two stressors: controlled chemical exposure and exercise. CS subjects will undergo chemical exposures in our Controlled Environment Facility (CEF) to assess their biologic and psychologic response to low-level exposure. CF subjects will undergo a maximal treadmill exercise test. Circadian patterns of catecholamines and axillary temperature, viral burden, and cardiovascular and endocrine reactivity will be measured in response to this physical stressor. Project 4 is an animal study evaluating the interaction between stress and pathology/physiology when rats are predisposed to disease by exposure to Soman or to Dioxin. Two strains of rats that differ in stress reactivity will be used to determine the interaction of hereditary factors and chemical exposure.

PURPOSE: To better understand the health problems of veterans of the Persian Gulf War by analyzing previous war-related illnesses and identifying possible unifying factors. DATA SOURCE: English-language articles and books on war-related illnesses published since 1863 that were located primarily through a manual search of bibliographies. DATA EXTRACTION: Publications were assessed for information on the clinical characteristics of war-related illnesses and the research methods used to evaluate such illnesses. DATA SYNTHESIS: Poorly understood war syndromes have been associated with armed conflicts at least since the U.S. Civil War. Although these syndromes have been characterized by similar symptoms (fatigue, shortness of breath, headache, sleep disturbance, forgetfulness, and impaired concentration), no single recurring illness that is unrelated to psychological stress is apparent. However, many types of illness were found among evaluated veterans, including well-defined medical and psychiatric conditions, acute combat stress reaction, post-traumatic stress disorder, and possibly the chronic fatigue syndrome. No single disease is apparent, but one unifying factor stands out: A unique population was intensely scrutinized after experiencing an exceptional, life-threatening set of exposures. As a result, research efforts to date have been unable to conclusively show causality, have been subject to reporting bias, and have lacked similar control populations. In addition to research limitations, war syndromes have involved fundamental, unanswered questions about the importance of chronic somatic symptoms and the factors that create a personal sense of ill health. CONCLUSION: Until we can better understand what constitutes health and illness in all adult populations, we risk repeated occurrences of unexplained symptoms among veterans after each war.

A neuropsychological investigation of 21 Persian Gulf veterans and 38 demographically matched controls was conducted in order to make a preliminary determination concerning presence of neuropsychological deficits associated with the Persian Gulf War experience. The neuropsychological test battery consisted of measures of complex attention, memory, and motor skills previously shown to be sensitive to exposure to environmental toxins. It was found that the Persian Gulf veteran group did not demonstrate substantial impairment, but an impairment index derived from 14 test variables was statistically significantly different from controls in the direction of poorer performance.

The purpose of the New Jersey Center for Environmental Hazards Research is to define the illness referred to as Persian Gulf Syndrome (PGS). Our preliminary data indicated that more than half of the Persian Gulf Registry (PGR) veterans reported illness characterized by severe fatigue and symptoms consistent with chemical sensitivities. Therefore, our research approach focuses on investigations of veterans with chronic fatigue syndrome (CFS) and multiple chemical sensitivities (MCS). Project 1 is an epidemiological study of 2800 PGR veterans. Symptoms, indices of Chronic Fatigue (CF) and Chemical Sensitivity (CS), and risk factors will be surveyed with mailed questionnaires. Risk factors include demographics, past medical history, psychosocial variables, Gulf War experiences such as prophylactic medication use, occupational and environmental exposures, and pesticide exposures. Symptoms will be clustered to define Gulf War Syndromes. Significant associations between risk factors and these symptom clusters will also be investigated. Subjects identified as CF, CS, or both will be recruited into Projects 2 and 3. In Project 2, healthy veterans will be compared to veterans with CF, CS, and CF concurrent with CS. Veterans will undergo four studies: (1) viral-immunological, (2) psychiatric, psychological, behavioral, and neuropsychological, (3) autonomic dysregulation, and (4) marker of P4501A2 induction resulting from exposure to combusting material. The purpose of Project 3 is to test the autonomic, immunologic, neuropsychologic, and psychologic responses of veterans with CS or CF to two stressors: controlled chemical exposure and exercise. CS subjects will undergo chemical exposures in our Controlled Environment Facility (CEF) to assess their biologic and psychologic response to low-level exposure. CF subjects will undergo a maximal treadmill exercise test. Circadian patterns of catecholamines and axillary temperature, viral burden, and cardiovascular and endocrine reactivity will be measured in response to this physical stressor. Project 4 is an animal study evaluating the interaction between stress and pathology/physiology when rats are predisposed to disease by exposure to Soman or to Dioxin. Two strains of rats that differ in stress reactivity will be used to determine the interaction of hereditary factors and chemical exposure.

In a pilot study, 14 Gulf War veterans were randomly selected from a large list of those with unexplained illness, to compare the functional integrity of the peripheral and central nervous system with a group of 13 healthy civilian control subjects using predetermined outcome measures. The controls were matched closely for age, sex, handedness, and physical activity. Outcome measures included scoring of symptoms and clinical neurological signs, quantitative sensory testing of heat, cold and vibration sensibilities, motor and sensory nerve conduction studies on upper and lower limbs, needle EMG of distal and proximal muscles and multimodality evoked potential (visual, brainstem, and somatosensory) studies. Three measurements, all related to peripheral nerve function (cold threshold (P = 0.0002), sural nerve latency (P = 0.034), and median nerve sensory action potential (P = 0.030) were abnormal in the veterans compared with the controls. There may be a dysfunction in the veterans but more studies are required to investigate the findings further and to characterise the dysfunction if confirmed.

Subjective sleep complaints and food intolerances, especially to milk products, are frequent symptoms of individuals who also report intolerance for low-level odors of various environmental chemicals. The purpose of the present study was to evaluate the objective nature of nocturnal sleep patterns during different diets, using polysomnography in community older adults with self-reported illness from chemical odors. Those high in chemical odor intolerance (n = 15) exhibited significantly lower sleep efficiency (p = .005) and lower rapid-eye- movement (REM) sleep percent (p = .04), with a trend toward longer latency to REM sleep (p = .07), than did those low in chemical intolerance (n = 15), especially on dairy-containing as compared with nondairy (soy) diets. The arousal pattern of the chemical odor intolerant group differed from the polysomnographic features of major depression, classical organophosphate toxicity, and subjective insomnia without objective findings. The findings suggest that community elderly with moderate chemical odor intolerance and minimal sleep complaints exhibit objectively poorer sleep than do their normal peers. Individual differences in underlying brain function may help generate these observations. The data support the need for similar studies in clinical populations with chemical odor intolerance, such as multiple chemical sensitivity patients and perhaps certain veterans with 'Persian Gulf Syndrome.'

Pyridostigmine, a carbamate acetylcholinesterase (AChE) inhibitor, is routinely employed in the treatment of the autoimmune disease myasthenia gravis. Pyridostigmine is also recommended by most Western armies for use as pretreatment under threat of chemical warfare, because of its protective effect against organophosphate poisoning. Because of this drug's quaternary ammonium group, which prevents its penetration through the blood-brain barrier, the symptoms associated with its routine use primarily reflect perturbations in peripheral nervous system functions. Unexpectedly, under a similar regimen, pyridostigmine administration during the Persian Gulf War resulted in a greater than threefold increase in the frequency of reported central nervous system symptoms. This increase was not due to enhanced absorption (or decreased elimination) of the drug, because the inhibition efficacy of serum butyryl-cholinesterase was not modified. Because previous animal studies have shown stress-induced disruption of the blood-brain barrier, an alternative possibility was that the stress situation associated with war allowed pyridostigmine penetration into the brain. Here we report that after mice were subjected to a forced swim protocol (shown previously to simulate stress), an increase in blood-brain barrier permeability reduced the pyridostigmine dose required to inhibit mouse brain AChE activity by 50% to less than 1/100th of the usual dose. Under these conditions, peripherally administered pyridostigmine increased the brain levels of c-fos oncogene and AChE mRNAs. Moreover, in vitro exposure to pyridostigmine increased both electrical excitability and c-fos mRNA levels in brain slices, demonstrating that the observed changes could be directly induced by pyridostigmine. These findings suggest that peripherally acting drugs administered under stress may reach the brain and affect centrally controlled functions.

Chemicals are introduced to fabric at many steps during manufacture and use. Fabrics containing chemicals can cause medical problems such as dermatitis and death. Insecticides impregnated into uniforms worn by 'Desert Storm' personnel are implicated in 'Gulf War Syndrome'. These chemicals must get from fabric into and through skin to cause toxic effects. The objective of the present study was to determine in vitro percutaneous absorption of model chemicals glyphosate (water soluble) and malathion (relative water insoluble) from cotton fabric into and through human skin. The percutaneous absorption of glyphosate from water solution was 1.42 +/- 0.25% dose. This decreased to 0.74 +/- 0.26% for glyphosate added to cotton sheets and immediately put onto skin. If the cotton sheets were dried for 1 or 2 days, then applied to skin, absorption was 0.08 +/- 0.02% and 0.08 +/- 0.01% respectively. However, wetting the 2-day dried cotton sheet with water to simulate sweating or wet conditions increased absorption to 0.36 +/- 0.07%. Similar results were found for malathion. Absorption of malathion from aqueous ethanol solution was 8.77 +/- 1.43%. This decreased to 3.92 +/- 0.49%, 0.62 +/- 0.11% and 0.60 +/- 0.14% for 0, 1- and 2-day-treated cotton sheets. However, malathion absorption from 2-day treated/dried cotton sheets increased to 7.34 +/- 0.61% when wetted with aqueous ethanol. These results show that chemicals in fabric (clothing, rug, upholstery, etc.) can transfer from fabric into and through human skin to cause toxic effects.

Tripler Army Medical Center initiated the Department of Defense's Persian Gulf Illness Comprehensive Clinical Evaluation Program (CCEP) on June 15, 1994. In the first 5 months, 100 patients enrolled in this program. Sixteen (16%) were women who served in the Persian Gulf during Desert Shield/ Desert Storm, and 1 (1%) was the dependent wife of a Gulf War veteran who is experiencing illness that may be related to the Persian Gulf War. All 17 women enrolled in the CCEP were evaluated in the Tripler Army Medical Center Obstetrics and Gynecology Clinic between June 17 and November 10, 1994. Each patient underwent gynecologic history, pelvic exam, Pap smear, and screen for fecal occult blood. Ten patients underwent baseline mammograms and 13 patients underwent urogenital and cervical cultures for aerobic bacteria, chlamydia and herpes simplex. The 1 patient with an abnormal Pap smear underwent cervical and endocervical biopsies and colposcopy (histology demonstrated no dysplasia or neoplasia). Half of the 16 Gulf War veterans experienced gynecologic problems while serving in the Gulf and 43% admitted gynecologic problems since returning in 1991. Of 6 patients who became pregnant after returning, 5 had normal pregnancies and 1 suffered four miscarriages.

In order to answer the questions arising from the health concerns of Gulf veterans, the Defence Medical Services have collated relevant health data so that they may be systematically analysed. However, data coverage is limited and there are concerns about its quality. Intramural studies alone will not be robust enough to determine of veterans are experiencing an excess of ill-health so a programme of epidemiological studies will be commissioned in collaboration with the Medical Research Council.

Some Canadians who served in the military in the Persian Gulf 4 years ago complain of a range of symptoms commonly described as Gulf War syndrome. Although the syndrome is not recognized as a clinical entity, symptoms include fatigue, lack of sleep, depression, cognitive problems, rashes, bone aches, lassitude, lack of motivation, forgetfulness, mood changes irritability and diarrhea. The medical branch of the Department of National Defence has established programs to inform, guide diagnosis and reach out to symptomatic veterans of the Persian Gulf conflict. Civilian physicians who provide similar care to military personnel who participated in the conflict are invited to call the medical branch (613 996-3752) for further information.

In November 1994, the U.S. Department of Veterans' Affairs (VA), the Department of Defense (DoD), and the Pennsylvania Department of Health requested that CDC investigate a report of unexplained illnesses among members of an Air National Guard (ANG) unit in south-central Pennsylvania (Unit A) who were veterans of the Persian Gulf War (PGW) (August 1990-June 1991). These veterans had been evaluated at a local VA medical center for symptoms that included recurrent rash, diarrhea, and fatigue. A three-stage investigation was planned to 1) verify and characterize signs and symptoms in PGW veterans attending the VA medical center; 2) determine whether the prevalence of symptoms was higher among members of Unit A than among members of other units deployed to the PGW and, if so, whether the increased prevalence was associated with PGW deployment; and 3) characterize the illness and identify associated risk factors. This report presents preliminary findings from stages 1 and 2 (stage 3 is in progress).

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