Organophosphates dysregulate dopamine signaling, glutamatergic neurotransmission, and induce neuronal injury markers in striatum

The neurological effects of organophosphate (OP) pesticides, commonly used on foods and in households, are an important public health concern. Furthermore, subclinical exposure to combinations of organophosphates is implicated in Gulf War illness. Here, we characterized the effects of the broadly used insecticide chlorpyrifos (CPF) on dopamine and glutamatergic neurotransmission effectors in corticostriatal motor/reward circuitry. CPF potentiated protein kinase A (PKA)-dependent phosphorylation of the striatal protein dopamine- and cAMP-regulated phosphoprotein of M(r) 32 kDa (DARPP-32) and the glutamate receptor 1 (GluR1) subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in mouse brain slices. It also increased GluR1 phosphorylation by PKA when administered systemically. This correlated with enhanced glutamate release from cortical projections in rat striatum. Similar effects were induced by the sarin congener, diisopropyl fluorophosphate, alone or in combination with the putative neuroprotectant, pyridostigmine bromide and the pesticide N,N-diethyl-meta-toluamide (DEET). This combination, meant to mimic the neurotoxicant exposure encountered by veterans of the 1991 Persian Gulf War, also induced hyperphosphorylation of the neurofibrillary tangle-associated protein tau. Diisopropyl fluorophosphate and pyrodostigmine bromide, alone or in combination, also increased the aberrant activity of the protein kinase, Cdk5, as indicated by conversion of its activating cofactor p35 to p25. Thus, consistent with recent findings in humans and animals, organophosphate exposure causes dysregulation in the motor/reward circuitry and invokes mechanisms associated with neurological disorders and neurodegeneration.     

Age-related changes of element contents in human mitral and tricuspid valves

To examine age-related changes of human cardiac valves, mitral and tricuspid valves were analyzed by inductively coupled plasma-atomic emission spectrometry. The subjects for mitral valves consisted of 12 men and 8 women, ranging in age from 52 to 96 yr. The subjects for tricuspid valves consisted of 11 men and 6 women, ranging in age from 52 to 93 yr. Furthermore, 16 of the samples of the cardiac valves were derived from the same subjects. The contents of calcium, phosphorus, and magnesium in the mitral valves increased progressively with advancing age and reached maximum in the 80s in regard to calcium and phosphorus and maximum in the 90s in regard to magnesium. The maximum average amounts corresponded to about three times the average contents in the 60s. In contrast, the content of sulfur in the mitral valves remained constant between the 50s and 90s. Regarding tricuspid valve, the contents of calcium, phosphorus, and magnesium scarcely increased with advancing age, except for one subject who died of chronic renal failure. Histological observations of the mitral valves revealed that deposits of calcium were present in both the elastic fibers and its degenerative tissues of the mitral valve. The present study indicates that the accumulation of calcium, phosphorus, and magnesium occurs progressively in the mitral valve with aging, but does not occur in the tricuspid valve.     

Neurotoxicity of depleted uranium

Depleted uranium (DU) is a byproduct of the enrichment process of uranium for its more radioactive isotopes to be used in nuclear energy. Because DU is pyrophoric and a dense metal with unique features when combined in alloys, it is used by the military in armor and ammunitions. There has been significant public concern regarding the use of DU by such armed forces, and it has been hypothesized to play a role in Gulf War syndrome. In light of experimental evidence from cell cultures, rats, and humans, there is justification for such concern. However, there are limited data on the neurotoxicity of DU. This review reports on uranium uses and its published health effects, with a major focus on in vitro and in vivo studies that escalate concerns that exposure to DU might be associated with neurotoxic health sequelae.     

Heart valve macro- and microstructure

Each heart valve is composed of different structures of which each one has its own histological profile. Although the aortic and the pulmonary valves as well as the mitral and the tricuspid valves show similarities in their architecture, they are individually designed to ensure optimal function with regard to their role in the cardiac cycle.In this article, we systematically describe the structural elements of the four heart valves by different anatomical, light- and electron-microscopic techniques that have been presented. Without the demand of completeness, we describe main structural features that are in our opinion of importance in understanding heart valve performance. These features will also have important implications in the treatment of heart valve disease. They will increase the knowledge in the design of valve substitutes or partial substitutes and may participate to improve reconstructive techniques. In addition, understanding heart valve macro- and microstructure may also be of benefit in heart valve engineering techniques.     

A fatal case of fungal endocarditis of the tricuspid valve associated with long-term venous catheterization and treatment with antibiotics in a patient with a history of alcohol abuse

We report a fatal case of fungal (candidal) endocarditis of the tricuspid valve with clinico-pathologically interesting findings following and associated with candidal pneumonia during long-term central venous catheterization (CVC) for intravenous therapy and long-term treatment with antibiotics for bacterial and fungal infection in a patient with a history of alcohol abuse. We review the literature on fungal cardiac infection related to long-term catheterization and alcohol abuse, and discuss the pathogenesis. This revised version was published online in June 2006 with corrections to the Cover Date.     

Gulf War Syndrome: A Reaction to Psychiatry’s Invasion of the Military?

Following the 1991 Gulf War, a number of soldiers who fought there began to complain of various symptoms and disorders, the collection of which came to be known as Gulf War syndrome (GWS). A debate has raged about the nature and cause of this illness, with many suggesting that it is a psychiatric condition. GWS continues to be a contested illness, yet there is no disputing that many Gulf veterans are ill. This article considers the way in which GWS sufferers understand their illness to be physical in nature and the way in which they negotiate and resist psychological theories of their illness. Based on 14 months of ethnographic fieldwork in the United Kingdom, data for this article were collected mainly by in-depth, semistructured interviews with GWS sufferers, their family members, doctors, and scientists, as well as healthy Gulf veterans. A total of 93 informants were interviewed, including 67 UK Gulf veterans, most of whom were ill. The paper argues that despite the increasing presence of psychiatry in military discourse, GWS reveals the way that people are able to transform, negotiate and even negate its power and assumptions.     

Premature Mortality in the Kingdom of Saudi Arabia Associated with Particulate Matter Air Pollution from the 1991 Gulf War

The State of Kuwait oil fires and military operations associated with the 1991 Gulf War resulted in substantially increased levels of airborne particulate matter (PM) in the Kingdom of Saudi Arabia (KSA) during 1991 and 1992. Using quantitative risk assessment methodology, this article estimates the increase in premature deaths in citizens of the KSA associated with the Gulf War–related increase in PM air pollution levels. Meta-analysis of daily time-series studies of non-accidental mortality associated with increased PM₁₀ levels using two alternative methodologies yielded exposure-response relative risk functions of 2.7% and 3.5% per 50 μ g/m³ increase in PM₁₀ concentration. Combining these exposure-response functions with estimates of the magnitude and duration of the increased PM₁₀ exposure, the size of the exposed population and baseline mortality rates provided an estimate of approximately 1,080 to 1,370 excess non-accidental deaths of Saudi citizens during 1991–1992 associated with the Gulf War–related increase in PM levels.     

Single site pacing through the anterior interventricular vein in a patient with a mechanic tricuspid valve

Transvenous endocardial pacing through classical implantation of a pace/sensing lead in the right ventricle is strictly contraindicated in patients with a mechanical tricuspid valve. Usually permanent pacing is achieved by an epimyocardial surgical approach. We hereby describe the implantation of a single site left ventricle pacing lead in the anterior interventricular vein in a 60 year-old woman with symptomatic bradycardia, permanent atrial fibrillation, and mechanical tricuspid valve. The described use of left ventricle pacing through a coronary vein lead, in a patient with favorable venous anatomy, provided (through a minimal invasive approach) effective with a low and stable threshold.     

Dysbiosis in gastrointestinal pathophysiology: Role of the gut microbiome in Gulf War Illness

Gulf War Illness (GWI) has been reported in 25%–35% of veterans returned from the Gulf war. Symptoms of GWI are varied and include both neurological and gastrointestinal symptoms as well as chronic fatigue. Development of GWI has been associated with chemical exposure particularly with exposure to pyridostigmine bromide (PB) and permethrin. Recent studies have found that the pathology of GWI is connected to changes in the gut microbiota, that is the gut dysbiosis. In studies using animal models, the exposure to PB and permethrin resulted in similar changes in the gut microbiome as these found in GW veterans with GWI. Studies using animal models have also shown that phytochemicals like curcumin are beneficial in reducing the symptoms and that the extracellular vesicles (EV) released from gut bacteria and from the intestinal epithelium can both promote diseases and suppress diseases through the intercellular communication mechanisms. The intestinal epithelium cells produce EVs and these EVs of intestinal epithelium origin are found to suppress inflammatory bowel disease severity, suggesting the benefits of utilizing EV in treatments. On the contrary, EV from the plasma of septic mice enhanced the level of proinflammatory cytokines in vitro and neutrophils and macrophages in vivo, suggesting differences in the EV depending on the types of cells they were originated and/or influences of environmental changes. These studies suggest that targeting the EV that specifically have positive influences may become a new therapeutic strategy in the treatment of veterans with GWI.     

Aluminum hydroxide injections lead to motor deficits and motor neuron degeneration

Gulf War Syndrome is a multi-system disorder afflicting many veterans of Western armies in the 1990–1991 Gulf War. A number of those afflicted may show neurological deficits including various cognitive dysfunctions and motor neuron disease, the latter expression virtually indistinguishable from classical amyotrophic lateral sclerosis (ALS) except for the age of onset. This ALS “cluster” represents the second such ALS cluster described in the literature to date. Possible causes of GWS include several of the adjuvants in the anthrax vaccine and others. The most likely culprit appears to be aluminum hydroxide. In an initial series of experiments, we examined the potential toxicity of aluminum hydroxide in male, outbred CD-1 mice injected subcutaneously in two equivalent-to-human doses. After sacrifice, spinal cord and motor cortex samples were examined by immunohistochemistry. Aluminum-treated mice showed significantly increased apoptosis of motor neurons and increases in reactive astrocytes and microglial proliferation within the spinal cord and cortex. Morin stain detected the presence of aluminum in the cytoplasm of motor neurons with some neurons also testing positive for the presence of hyper-phosphorylated tau protein, a pathological hallmark of various neurological diseases, including Alzheimer’s disease and frontotemporal dementia. A second series of experiments was conducted on mice injected with six doses of aluminum hydroxide. Behavioural analyses in these mice revealed significant impairments in a number of motor functions as well as diminished spatial memory capacity. The demonstrated neurotoxicity of aluminum hydroxide and its relative ubiquity as an adjuvant suggest that greater scrutiny by the scientific community is warranted.     

Vaccination alone or in combination with pyridostigmine promotes and prolongs activation of stress-activated kinases induced by stress in the mouse brain

Gulf war illnesses (GWI) are currently affecting thousands of veterans. To date, the molecular mechanisms underlying the pathogenesis of these illnesses remain unknown. During Gulf war I, military personnel were exposed to multiple stressors, one or more vaccines, pyridostigmine (PY), and other chemicals. In our previous studies, we found that stress induces activation of mitogen activated protein-kinase kinase 4 (MKK4) and c-Jun-N-terminal kinase (JNK) in the mouse brain (Liu et al. 2004). Our working hypothesis is that stress, vaccination, and PY may synergistically induce activation of MKK4 and JNK in the brain, leading to over-activation of these kinases and neurological injuries. To test our hypothesis, we examined the effect of keyhole limpet hemocyanin (KLH) immunization alone or in combination with PY on activation of MKK4 and JNK induced by stress. We found that KLH immunization alone had a small effect on MKK4 or JNK activity but it significantly enhanced and prolonged activation of these kinases induced by stress, from a few hours to several days. Additionally, KLH immunization caused activation of p38MAPK. PY treatment further enhanced and prolonged activation of these kinases induced by stress in combination with KLH immunization and triggered activation of caspase-3. Our current studies suggest that stress, vaccination, and PY may synergistically act on multiple stress-activated kinases in the brain to cause neurological impairments in GWI.     

Brain accumulation of depleted uranium in rats following 3- or 6-month treatment with implanted depleted uranium pellets

Depleted uranium (DU) is used to reinforce armor shielding and increase penetrability of military munitions. Although the data are conflicting, DU has been invoked as a potential etiological factor in Gulf War syndrome. We examined regional brain DU accumulation following surgical implantation of metal pellets in male Sprague-Dawley rats for 3 or 6 mo. Prior to surgery, rats were randomly divided into five groups: Nonsurgical control (NS Control); 0 DU pellets/20 tantalum (Ta) pellets (Sham); 4 DU pellets/16 Ta pellets (Low); 10 DU pellets/10 Ta pellets (Medium); 20 DU pellets/0 Ta pellets (High). Rats were weighed weekly as a measure of general health, with no statistically significant differences observed among groups in either cohort. At the conclusion of the respective studies, animals were perfused with phosphate-buffered saline, pH 7.4, to prevent contamination of brain tissue with DU from blood. Brains were removed and dissected into six regions: cerebellum, brainstem (pons and medulla), midbrain, hippocampus, striatum, and cortex. The uranium content was measured in digested samples as its ²³⁸U isotope by high-resolution inductively coupled plasma-mass spectrometry. After 3 mo postimplantation, DU significantly accumulated in all brain regions except the hippocampus in animals receiving the highest dose of DU (p<0.05). By 6 mo, however, significant accumulation was measured only in the cortex, midbrain, and cerebellum (p<0.01). Our data suggest that DU implanted in peripheral tissues can preferentially accumulate in specific brain regions.     

Pharmacologically increasing microtubule acetylation corrects stress‐exacerbated effects of organophosphates on neurons

Many veterans of the 1990‐1991 Gulf War contracted Gulf War Illness (GWI), a multisymptom disease that primarily affects the nervous system. Here, we treated cultures of human or rat neurons with diisopropyl fluorophosphate (DFP), an analog of sarin, one of the organophosphate (OP) toxicants to which the military veterans were exposed. All observed cellular defects produced by DFP were exacerbated by pretreatment with corticosterone or cortisol, which, in rat and human neurons, respectively, serves in our experiments to mimic the physical stress endured by soldiers during the war. To best mimic the disease, DFP was used below the level needed to inhibit acetylcholinesterase. We observed a diminution in the ratio of acetylated to total tubulin that was correctable by treatment with tubacin, a drug that inhibits HDAC6, the tubulin deacetylase. The reduction in microtubule acetylation was coupled with deficits in microtubule dynamics, which were correctable by HDAC6 inhibition. Deficits in mitochondrial transport and dopamine release were also improved by tubacin. Thus, various negative effects of the toxicant/stress exposures were at least partially correctable by restoring microtubule acetylation to a more normal status. Such an approach may have therapeutic benefit for individuals suffering from GWI or other neurological disorders linked to OP exposure.      

Reconstructing historical baselines for the Persian/Arabian Gulf Dugong,Dugong dugon (Mammalia: Sirena)

Retrospective estimates of historic abundances and distributions of marine organisms are crucial to understanding the anthropogenic impacts on the structure and species of coastal ecosystems, especially in the case of vulnerable species such as the Dugong (Dugong dugon). The Persian/Arabian Gulf is home to the second largest Dugong population in the world, yet little is known about their current or past abundance, distribution, and ecological role. Here, we examine historical changes in dugong distribution and estimate perceived changes in their abundance. We create a ‘dugong discovery curve’ and compile global density estimates as proxies for the overall health of the population in the Gulf. We find that since 1950 dugong range may have contracted by one quarter, and despite their large population, their overall densities in the Gulf are far lower than in other areas within their range. Basic understanding of historical trajectories for Dugongs is needed in order to develop appropriate management plans and conservation targets, particularly in light of large and wide-spread coastal development projects in the region.     

Are artificial reefs surrogates of natural habitats for corals and fish in Dubai,United Arab Emirates?

Artificial reefs are often promoted as mitigating human impacts in coastal ecosystems and enhancing fisheries; however, evidence supporting their benefits is equivocal. Such structures must be compared with natural reefs in order to assess their performance, but past comparisons typically examined artificial structures that were too small, or were immature, relative to the natural reefs. We compared coral and fish communities on two large (>400,000 m³) and mature (>25 year) artificial reefs with six natural coral patches. Coral cover was higher on artificial reefs (50%) than in natural habitats (31%), but natural coral patches contained higher species richness (29 vs. 20) and coral diversity (H′ = 2.3 vs. 1.8). Multivariate analyses indicated strong differences between coral communities in natural and artificial habitats. Fish communities were sampled seasonally for 1 year. Multivariate fish communities differed significantly among habitat types in the summer and fall, but converged in the winter and spring. Univariate analysis indicated that species richness and abundance were stable throughout the year on natural coral patches but increased significantly in the summer on artificial reefs compared with the winter and spring, explaining the multivariate changes in community structure. The increased summer abundance on artificial reefs was mainly due to adult immigration. Piscivores were much more abundant in the fall than in the winter or spring on artificial reefs, but had low and stable abundance throughout the year in natural habitats. It is likely that the decreased winter and spring abundance of fish on the artificial reefs resulted from both predation and emigration. These results indicate that large artificial reefs can support diverse and abundant coral and fish communities. However, these communities differ structurally and functionally from those in natural habitats, and they should not be considered as replacements for natural coral and fish communities.     

Bearing Witness: Assumptions, Realities, and the Otherizing of Katrina

As post-Katrina rebuilding of Louisiana and Mississippi proceeds, we should heed the lessons from anthropologists and others studying aid and development in other parts of the world who point out that aid is often predicated on poorly examined assumptions about beneficiaries and local conditions. Hence, as the recovery after Katrina continues, assumptions about the U.S. South and about poverty, race, and class in the United States must be exposed and examined as well as assumptions about disaster victims and relief. Drawing on personal experiences, I examine here some of the assumptions with which I operated as a small group of friends and I organized an unofficial relief team to provide whatever aid we could to people on the Mississippi Gulf coast in the first few weeks after Hurricane Katrina. I recount the disconnections between my assumptions and the local conditions as relayed by Katrina survivors or that members of the team and I witnessed firsthand.     

Chemosymbiotic bivalves from the mud volcanoes of the Gulf of Cadiz, NE Atlantic, with descriptions of new species of Solemyidae, Lucinidae and Vesicomyidae

The chemosymbiotic bivalves collected from the mud volcanoes of the Gulf of Cadiz are reviewed. Of the thirteen species closely associated with chemosynthetic settings two Solemyidae, Solemya (Petrasma) elarraichensissp. n. and Acharax gadiraesp. n., one Lucinidae, Lucinoma asapheussp. n., and one Vesicomyidae, Isorropodon megadesmussp. n. are described and compared to close relatives of their respective families. The biodiversity and distribution of the chemosymbiotic bivalves in the Gulf of Cadiz are discussed and compared to the available information from other cold seeps in the Eastern Atlantic and Mediterranean. Although there is considerable similarity at the genus level between seep/mud volcano fields in the Eastern Atlantic and Mediterranean, there is little overlap at the species level. This indicates a high degree of endemism within chemosymbiotic bivalve assemblages.