Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1998-11-16
2001-04-10
Park, Hankyel T. (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S039000, C530S387100
Reexamination Certificate
active
06214566
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to methods and immunoassay kits that are useful to aid in the diagnosis of Gulf War Syndrome (GWS). A correlation between the presence of antisqualene antibodies and incidence of GWS has been discovered. Development of methods for the detection of antisqualene antibodies in a test sample facilitates the diagnosis of GWS.
BACKGROUND OF THE INVENTION
The illnesses afflicting men and women who served in the Persian Gulf military conflict during 1990-1991 remain ill-defined. A constellation of symptoms including fatigue, rashes, headaches, arthralgias, myalgias, diarrhea, memory loss, autoimmune thyroid disease, increased allergies and sensitivities to environmental elements, and neurological abnormalities collectively referred to as Gulf War Syndrome (GWS) have been described (Grady, et al.
Arch. Int. Med.
158: 367-371, 1998; Persian Gulf Veterans Coordinating Board.
Arch. Int. Med.
155: 262-268, 1995; Haley, et al.
J.A.M.A.
277: 231-237, 1997). While GWS patients do not in general suffer from classic rheumatic diseases, the signs and symptoms are reminiscent of atypical connective tissue diseases such as fibromyalgia, chronic fatigue syndrome, and the process associated with exposure to silicone breast implants (SBI). Serological abnormalities including hypergammaglobulinemia and abnormal serum proteins have been reported in 45% of GWS patients (Grady, et al.
Arch. Int. Med.
158: 367-371, 1998).
Hundreds of explanations for GWS have been proposed. In 1994, the U.S. Secretary of Defense and the Secretary of Veterans Affairs asked the Center for Disease Control and Prevention to conduct an official scientific study exploring possible causes of GWS. The study was aimed at organizing reported symptoms into a defined case, characterizing clinical features, and evaluating risk factors. The results are described by Fukuda, et al (
J.A.M.A.
280: 981-988, 1998). Fukuda et al, assessed a population of Gulf War Veterans with respect to many of the proposed explanations for GWS. The study included assessment of physical symptoms; blood, urine, and stool analysis; and
serological assays. Tests were conducted to detect the presence of various viruses, bacteria, mycoplasm, and parasites. Serum was tested for yellow fever, dengue, Sindbis, West Nole, and phlebotomus fever viruses (Naples and Sicilian); Toscana, Karimbad, and Isfahan viruses;
Rickettsia typhi
and
Rickettsia rickettsii; Coxiellla burnetii; Ehrlichia chaffeensis; Leishmania tropica
and
Leishmania donovani; Toxoplasma gondii; Schistosoma mansoni
and
Schistosoma haematobium; Strongyloides stercoralis; Helibacter pylori; Clostridium botulinum;
and
Bacillus anthracis.
Stool specimens were tested for red and white blood cells; ova and parasites of
Cryptosporidium parvum, Cyclospora cayetanensis, Isospora belli,
and microsporidia; enteroviruses; and bacteria strains of Salmonella, Shigella, Yersinia, Campylobacter, and
Escherichia coli
(0157:H7). While this study is considered an official and comprehensive report on GWS, no attempt was made to assess alternative explanations, such as adjuvant's disease.
Other theories, implicating exposure to chemical and biological agents as a cause of GWS, have been the subject of numerous studies. These studies, however, neither conclusively identify a causative agent for the disease nor properly explain the pathology observed in GWS cases.
The Persian Gulf Veterans Coordinating Board has addressed the possibility of exposures to chemical and biological agents. The Board, however, attempted to account for these illnesses without defining a molecular pathology (Persian Gulf Veterans Coordinating Board.
Arch. Int. Med.
155: 262-268, 1995).
Haley grouped reported symptoms into seven different syndromes based upon possible exposure to various chemicals present at the time of the Persian Gulf Conflict (Haley, et al.
J.A.M.A.
277: 231-237, 1997). While this study does attempt to categorize possible causes of the disease, it fails to explain the GWS pathology observed in the veterans. Furthermore, the study did not outline the pathology one would expect to observe in those exposed to the various chemical agents.
Abou-Donia examined acute toxicity of pyridostygmine bromide and organophosphates in chickens (Abou-Donia, et al.
J. Tox. Environ. Health.
48: 35-56, 1996). The study compared chickens suffering from acute toxicity to the condition presented by GWS patients. However, since many Gulf War veterans did not develop GWS until months or years after the military conflict, an animal model which employs a rapid acute response to mimic the symptoms of GWS may not be appropriate. As a result, the study examining acute toxicity in chickens may not be relevant to a human disease characterized by a delayed onset. Furthermore, the study did not fully reflect the molecular pathology observed in actual GWS cases.
While chemical toxicity may mimic some of the GWS symptoms, it cannot account for all of them. For instance, exposure to organophosphates has never been associated with the development of immunological abnormalities (Vial, et al.
J. Tox. Environ. Health.
48: 215-229, 1996). Chronic organophosphate pesticide intoxication in two mammalian species neither interfered with cell-mediated immunity, nor induced autoimmunity (Jha, et al.
Acta. Vet. Hung
38: 55-60, 1990). Clearly, this is distinct from GWS, which displays a multitude of symptoms linked to immune dysfunction.
An additional example involving chemical agents is provided by the large numbers of individuals exposed to sarin in the Japanese subway Mar. 20, 1995. Acetylcholinesterase levels were monitored and observed to return to normal levels in all patients by three months following exposure. Some subclinical miosis and neuropathy were present 30 days after exposure, but these disappeared after a year (Morita, et al.
Lancet.
346: 290-3, 1995). Tissue distribution of sarin and its metabolites, as well as the time course of detoxification following exposure is known (Little, et al.
Toxicol. Appl. Pharmacol.
83: 412-419, 1986). The physiological effects are immediate and the pathology is well documented. In no case has there been reports of any delayed onset of autoimmune disorders.
No exposures to chemical agents which required medical treatment were documented by U. S. military personnel. Such exposures typically require the use of ventilatory or circulatory supports, or atropine and anticonvulsants to combat the onset of acute symptoms. Low dose effects were also not observed (Dr. Bernard Rostker, Pentagon, personal communication; Col. Edward Koenigsburg, USAF, Persian Gulf Investigation, Falls Church, Va., personal communication). Such effects have been studied in primates and generally abate within 24 hours of the exposure (Wolthuis, et al.
Pharmacol. Biochem. Behav.
51: 443-456,1995).
Others have proposed that GWS is a type of post-traumatic stress syndrome (Hyams, et al.
Ann. Int. Med.
125: 398-405, 1996). It is difficult, however, to reconcile this hypothesis with the symptoms manifest in afflicted individuals.
An additional explanation has been outlined in which GWS results from a dysregulation of the immune system. (Hyams, et al.
Ann. Int. Med.
125: 398-405, 1996). The GWS patients suffer from various symptoms similar to those having autoimmune diseases, but cannot be diagnosed with a “classic” rheumatic disease. Gulf War veterans and attendant civilian personnel received a variety of immunizations in preparation for possible deployment to the Persian Gulf theater (David, et al.
Br. Med. J
314: 239-240, 1997). It has been suggested that GWS may result from an imbalance in the immune system. It was hypothesized that the imbalance may be due to an adverse reaction to a vaccination.
It was noted in some patients that the onset of illness occurred within weeks of receiving a full complement of immunizations. These individuals displayed symptoms of GWS soon after vaccination and were not deployed. Other individuals were deployed, but returned home before the
Asa Pamela B.
Garry Robert F.
Howrey Simon Arnold & White , LLP
Park Hankyel T.
The Administrators of the Tulane Educational Fund
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