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      Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment

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          Abstract

          Veterans of Operation Desert Storm/Desert Shield – the 1991 Gulf War (GW) – are a unique population who returned from theater with multiple health complaints and disorders. Studies in the U.S. and elsewhere have consistently concluded that approximately 25–32% of this population suffers from a disorder characterized by symptoms that vary somewhat among individuals and include fatigue, headaches, cognitive dysfunction, musculoskeletal pain, and respiratory, gastrointestinal and dermatologic complaints. Gulf War illness (GWI) is the term used to describe this disorder. In addition, brain cancer occurs at increased rates in subgroups of GW veterans, as do neuropsychological and brain imaging abnormalities.

          Chemical exposures have become the focus of etiologic GWI research because nervous system symptoms are prominent and many neurotoxicants were present in theater, including organophosphates (OPs), carbamates, and other pesticides; sarin/cyclosarin nerve agents, and pyridostigmine bromide (PB) medications used as prophylaxis against chemical warfare attacks. Psychiatric etiologies have been ruled out.

          This paper reviews the recent literature on the health of 1991 GW veterans, focusing particularly on the central nervous system and on effects of toxicant exposures. In addition, it emphasizes research published since 2008, following on an exhaustive review that was published in that year that summarizes the prior literature ( RACGWI, 2008).

          We conclude that exposure to pesticides and/or to PB are causally associated with GWI and the neurological dysfunction in GW veterans. Exposure to sarin and cyclosarin and to oil well fire emissions are also associated with neurologically based health effects, though their contribution to development of the disorder known as GWI is less clear. Gene-environment interactions are likely to have contributed to development of GWI in deployed veterans. The health consequences of chemical exposures in the GW and other conflicts have been called “toxic wounds” by veterans. This type of injury requires further study and concentrated treatment research efforts that may also benefit other occupational groups with similar exposure-related illnesses.

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          Most cited references155

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          Control of microglial neurotoxicity by the fractalkine receptor.

          Microglia, the resident inflammatory cells of the CNS, are the only CNS cells that express the fractalkine receptor (CX3CR1). Using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity. Following peripheral lipopolysaccharide injections, Cx3cr1-/- mice showed cell-autonomous microglial neurotoxicity. In a toxic model of Parkinson disease and a transgenic model of amyotrophic lateral sclerosis, Cx3cr1-/- mice showed more extensive neuronal cell loss than Cx3cr1+ littermate controls. Augmenting CX3CR1 signaling may protect against microglial neurotoxicity, whereas CNS penetration by pharmaceutical CX3CR1 antagonists could increase neuronal vulnerability.
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            Acetylcholinesterase inhibitors and Gulf War illnesses.

            Increasing evidence suggests excess illness in Persian Gulf War veterans (GWV) can be explained in part by exposure of GWV to organophosphate and carbamate acetylcholinesterase inhibitors (AChEis), including pyridostigmine bromide (PB), pesticides, and nerve agents. Evidence germane to the relation of AChEis to illness in GWV was assessed. Many epidemiological studies reported a link between AChEi exposure and chronic symptoms in GWV. The link is buttressed by a dose-response relation of PB pill number to chronic symptoms in GWV and by a relation between avidity of AChEi clearance and illness, based on genotypes, concentrations, and activity levels of enzymes that detoxify AChEis. Triangulating evidence derives from studies linking occupational exposure to AChEis to chronic health symptoms that mirror those of ill GWV. Illness is again linked to lower activity of AChEi detoxifying enzymes and genotypes conferring less-avid AChEi detoxification. AChEi exposure satisfies Hill's presumptive criteria for causality, suggesting this exposure may be causally linked to excess health problems in GWV.
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              Mood and memory deficits in a model of Gulf War illness are linked with reduced neurogenesis, partial neuron loss, and mild inflammation in the hippocampus.

              Impairments in mood and cognitive function are the key brain abnormalities observed in Gulf war illness (GWI), a chronic multisymptom health problem afflicting ∼25% of veterans who served in the Persian Gulf War-1. Although the precise cause of GWI is still unknown, combined exposure to a nerve gas prophylaxis drug pyridostigmine bromide (PB) and pesticides DEET and permethrin during the war has been proposed as one of the foremost causes of GWI. We investigated the effect of 4 weeks of exposure to Gulf war illness-related (GWIR) chemicals in the absence or presence of mild stress on mood and cognitive function, dentate gyrus neurogenesis, and neurons, microglia, and astrocytes in the hippocampus. Combined exposure to low doses of GWIR chemicals PB, DEET, and permethrin induced depressive- and anxiety-like behavior and spatial learning and memory dysfunction. Application of mild stress in the period of exposure to chemicals exacerbated the extent of mood and cognitive dysfunction. Furthermore, these behavioral impairments were associated with reduced hippocampal volume and multiple cellular alterations such as chronic reductions in neural stem cell activity and neurogenesis, partial loss of principal neurons, and mild inflammation comprising sporadic occurrence of activated microglia and significant hypertrophy of astrocytes. The results show the first evidence of an association between mood and cognitive dysfunction and hippocampal pathology epitomized by decreased neurogenesis, partial loss of principal neurons, and mild inflammation in a model of GWI. Hence, treatment strategies that are efficacious for enhancing neurogenesis and suppressing inflammation may be helpful for alleviation of mood and cognitive dysfunction observed in GWI.
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                Author and article information

                Contributors
                Journal
                0100725
                3187
                Cortex
                Cortex
                Cortex; a journal devoted to the study of the nervous system and behavior
                0010-9452
                1973-8102
                22 December 2015
                25 September 2015
                January 2016
                24 January 2016
                : 74
                : 449-475
                Affiliations
                [a ]Department of Environmental Health, Boston University School of Public Health, Boston, MA, United States
                [b ]Baylor University Institute of Biomedical Studies, Waco, TX, United States
                [c ]Molecular Neurotoxicology, Toxicology & Molecular Biology Branch (MS-3014), Health Effects Laboratory Division, Centers for Disease Control and Prevention – NIOSH, Morgantown, WV, United States
                [d ]Boston University School of Public Health, Department of Environmental Health, Boston, MA, United States
                [e ]Research Advisory Committee on Gulf War Veterans’ Illnesses, Phoenix, AZ, United States
                [f ]University of California, San Diego, La Jolla, CA, United States
                [g ]Molecular & Integrative Neuroscience Department, The Scripps Research Institute, La Jolla, CA, United States
                [h ]National Gulf War Resource Center, Topeka, KS, United States
                [i ]Director, TBI Research Program, Roskamp Institute, Sarasota, FL, United States
                [j ]Captain, U.S. Army, Retired, Crestview, FL, United States
                [k ]Veterans for Common Sense, Bradenton, FL, United States
                [l ]Institute for Neuro-Immune Medicine, Nova Southeastern University, Miami, FL, United States
                [m ]McEntire Joint National Guard Base, Eastover, SC, United States
                [n ]Department of Emergency Medicine, 3ED311, The Brody School of Medicine, East Carolina University School of Medicine, Greenville, NC, United States
                [o ]U.S. Government Accountability Office, Salisbury, Wiltshire, UK
                [p ]School of Public Health, Ann Arbor, MI, United States
                [q ]Northeastern University, Department of Civil and Environmental Engineering, Boston, MA, United States
                Author notes
                [* ]Corresponding author: Department of Environmental Health, Boston University School of Public Health, 715 Albany St., T4W, Boston, MA 02118, United States
                Article
                HHSPA746360
                10.1016/j.cortex.2015.08.022
                4724528
                26493934
                5ee4c946-d112-4f30-abbb-31883c889ff1

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                Categories
                Article

                Neurology
                gulf war illness,pesticide,organophosphates,sarin,cyclosarin,veterans’ health
                Neurology
                gulf war illness, pesticide, organophosphates, sarin, cyclosarin, veterans’ health

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