MEDICAL RESEARCH ABSTRACTS THAT MIGHT HELP GULF WAR VETERANS

TRANSVERSE MELITIS-AUTOIMMUNE DISEASE------------Acute inflammation of Spinal Cord_____________________

Autoimmun Rev. 2009 Dec 24. [Epub ahead of print]
The epidemiology of transverse myelitis.
Bhat A, Naguwa S, Cheema G, Gershwin ME.Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA. Transverse myelitis is a neurological disorder causing acute spinal cord injury as a result of acute inflammation, often associated with para infectious processes and autoimmune disease. The purpose of this article is to review the literature on the geoepidemiology of transverse myelitis and assess its environmental associations. Articles from 1981 to 2009 were reviewed in Pub Med along with potential causes such as autoimmune disease (focusing on systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome (APS), and Sjogren's), infection, vaccination, and intoxication. Copyright © 2009 Elsevier B.V. All rights reserved. PMID: 20035902 [PubMed - as supplied by publisher]

______________________________GENE THERAPIES IN AUTOIMMUNE DISEASES__________________________________________________________________
Autoimmun Rev. 2009 Dec 24. [Epub ahead of print]
Development and validation of gene therapies in autoimmune diseases: Epidemiology to animal models.
Leung PS, Shu SA, Kenny TP, Wu PY, Tao MH.Division of Rheumatology/Allergy and Clinical Immunology, School of Medicine, University of California, Davis, CA 95616, United States. Recent advancement in immunology, molecular biology, and bioinformatics has yielded extensive information on the pathophysiological mechanisms of autoimmunity, which has greatly facilitated the identification of potential therapeutic targets and the development of gene therapy in the treatment of autoimmune disease. Preclinical studies were carried out in animal models. This phenomenon is well illustrated in two prototypic animal models of autoimmune disease: the autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS) and collagen-induced arthritis (CIA) model in rheumatoid arthritis (RA). Here we discuss the current data on the development and validation of gene therapy in autoimmunity in these two models. The success in preclinical animal model studies provides the proof-of-concept of gene therapy for potential future applications in the treatment of autoimmune diseases. Furthermore, the identification of risk factors from epidemiological studies reveals further potential therapeutic targets to be examined in animal models. Copyright © 2009. Published by Elsevier B.V.PMID: 20035901 [PubMed - as supplied by publisher]

---------------------NEUROINFLAMMATORY DISEASE>>>>>>>>>>>>>>>>>>>>>MS____________________________________________

Free Radic Biol Med. 2009 Dec 24. [Epub ahead of print]
Tempol ameliorates murine viral encephalomyelitis by preserving the blood-brain barrier, reducing viral load, and lessening inflammation. Tsuhako MH, Augusto O, Linares E, Chadi G, Giorgio S, Pereira CA.Laboratório de Imunologia Viral, Instituto Butantan, 05503-900 São Paulo, Brazil. Multiple sclerosis (MS) is a progressive inflammatory and/or demyelinating disease of the human central nervous system (CNS). Most of the knowledge about the pathogenesis of MS has been derived from murine models, such as experimental autoimmune encephalomyelitis and viral encephalomyelitis. Here, we infected female C57BL/6 mice with a neurotropic strain of the mouse hepatitis virus (MHV-59A) to evaluate whether treatment with the multifunctional antioxidant tempol (4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy) affects the ensuing encephalomyelitis. In untreated animals, neurological symptoms developed quickly: 90% of infected mice died 10 days after virus inoculation and the few survivors presented neurological deficits. Treatment with tempol (24 mg/kg, ip, two doses on the first day and daily doses for 7 days plus 2 mM tempol in the drinking water ad libitum) profoundly altered the disease outcome: neurological symptoms were attenuated, mouse survival increased up to 70%, and half of the survivors behaved as normal mice. Not surprisingly, tempol substantially preserved the integrity of the CNS, including the blood-brain barrier. Furthermore, treatment with tempol decreased CNS viral titers, macrophage and T lymphocyte infiltration, and levels of markers of inflammation, such as expression of inducible nitric oxide synthase, transcription of tumor necrosis factor-alpha and interferon-gamma, and protein nitration. The results indicate that tempol ameliorates murine viral encephalomyelitis by altering the redox status of the infectious environment that contributes to an attenuated CNS inflammatory response. Overall, our study supports the development of therapeutic strategies based on nitroxides to manage neuroinflammatory diseases, including MS. Copyright © 2009 Elsevier Inc. All rights reserved.PMID: 20035861 [PubMed - as supplied by publisher]

_________________________________AUTOIMMUNE DEMYELINATING DISEASE______________________________________________
Neurosci Lett. 2009 Dec 23. [Epub ahead of print]
TNF-alpha receptor 1 deficiency reduces antigen-presenting capacity of Schwann cells and ameliorates experimental autoimmune neuritis in mice. Mao XJ, Zhang XM, Zhang HL, Quezada HC, Mix E, Yang X, Winblad B, Adem A, Zhu J. Department of Neurology, the First Hospital of Jilin University, Changchun, China; Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden. Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic pro-inflammatory cytokine with potentially neurodestructive effects and plays a pivotal role in autoimmune demyelinating disease. To address the role of TNF-alpha in the pathogenesis of experimental autoimmune neuritis (EAN), the current study investigated the antigen-presenting capacity of Schwann cells (SCs) in EAN induced by P0 protein peptide 106-125 in TNF-alpha recepter 1 deficient (TNFR1(-/-)) mice. The antigen-presenting capacity of SCs was assessed by the expression of MHC class II (MHCII), CD40, CD80 and CD86 molecules on activated SCs as well as by induction of T cell proliferation in co-cultures of P0 protein peptide 106-125 specific T cells with activated SCs. In addition, the expression of inducible nitric oxide synthase (iNOS) was measured in activated SCs by flow cytometry. TNFR1(-/-) EAN mice developed significantly delayed and reduced clinical signs of EAN compared to wild type EAN mice. In parallel, the expression of MHCII, CD80 and iNOS on SCs were decreased in TNFR1(-/-) mice compared to wild type mice. Likewise, proliferation of P0 protein peptide 106-125 specific T cells simulated by activated SCs of TNFR1(-/-) EAN mice was lower than that of wild type EAN mice. Our data suggest that TNF-alpha may exert pro-inflammatory effects in EAN via TNFR1 by up-regulating the antigen-presenting function and iNOS production of SCs. Copyright © 2009. Published by Elsevier Ireland Ltd.PMID: 20035831 [PubMed - as supplied by publisher]

[Monoclonal antibodies in chronic autoimmune inflammatory diseases_________________________________________
Med Sci (Paris). 2009 Dec;25(12):1108-12.
[Monoclonal antibodies in chronic autoimmune inflammatory diseases.]
[Article in French] Semerano L, Boissier MC.
Université Paris 13, EA4222, Li2P, Bobigny, France. Assistance publique-hôpitaux de Paris, Service de rhumatologie, hôpital Avicenne, 125, rue de Stalingrad, 93017 Bobigny Cedex, France. Among chronic inflammatory diseases, rheumatoid arthritis is a common inflammatory and destructive arthropathy, characterized by the release of potent proinflammatory cytokines mostly TNFa and IL-1, which both mediate systemic effects and contribute to joint destruction. Many therapeutic agents have been proposed to antagonise these cytokines, among which monoclonal antibodies. Thus twenty years ago the anti-TNFa infliximab was the first monoclonal antibody to be proposed in a non-cancerous indication, rheumatoid arthritis. Since then, several other monoclonal antibodies and/or antagonists either targeting cytokines (IL-1, IL-6, RANKL), but also immune cellular effectors T and B cells, have been evaluated not only in rheumatoid arthritis, but also in systemic lupus, Crohn's disease, multiple sclerosis, or ankylosing spondylitis. Clinical benefit has been unambiguously demonstrated, but before these novel molecules enter routine clinical practice, several parameters will have to be accurately documented such as their safety, long term efficacy, and economical cost. double dagger.
PMID: 20035687 [PubMed - in process]

__________________INFLAMMATORY BOWEL DISEASE_______________________________________________________________
Biologics. 2009;3:77-97. Epub 2009 Jul 13.
Biologic targeting in the treatment of inflammatory bowel diseases. Bosani M, Ardizzone S, Porro GB.Chair of Gastroenterology, "L. Sacco", University Hospital, Milan, Italy. The etiology of inflammatory bowel disease (IBD) has not yet been clarified and immunosuppressive agents which nonspecifically reduce inflammation and immunity have been used in the conventional therapies for IBD. Evidence indicates that a dysregulation of mucosal immunity in the gut of IBD causes an overproduction of inflammatory cytokines and trafficking of effector leukocytes into the bowel, thus leading to an uncontrolled intestinal inflammation. Under normal situations, the intestinal mucosa is in a state of "controlled" inflammation regulated by a delicate balance of proinflammatory (tumor necrosis factor [TNF-alpha], interferon-gamma [IFN-gamma], interleukin-1 [IL-1], IL-6, IL-12 and anti-inflammatory cytokines IL-4, IL-10, IL-11). The mucosal immune system is the central effector of intestinal inflammation and injury, with cytokines playing a central role in modulating inflammation. Cytokines may therefore be a logical target for inflammatory bowel disease therapy using specific cytokine inhibitors. Biotechnology agents targeted against TNF, leukocyte adhesion, Th1 polarization, T cell activation, nuclear factor-kappaB (NF-kappaB), and other miscellaneous therapies are being evaluated as potential therapies for the treatment of inflammatory bowel disease. In this context, infliximab and adalimumab are currently the only biologic agents approved in Europe for the treatment of inflammatory Crohn's disease. Other anti-TNF biologic agents have emerged, including CDP571, certolizumab pegol, etanercept, onercept. However, ongoing research continues to generate new biologic agents targeted at specific pathogenic mechanism involved in the inflammatory process. Lymphocyte-endothelial interactions mediated by adhesion molecules are important in leukocyte migration and recruitment to sites of inflammation, and selective blockade of these adhesion molecules is a novel and promising strategy to treat Crohn's disease. Therapeutics agents to inhibit leukocyte trafficking include natalizumab (approved for use in Crohn's disease in USA), MLN-02, and ISIS 2302. Other agents being investigated for the treatment of Crohn's disease include inhibitors of T cell activation, proinflammatory cytokine receptors, Th1 polarization, growth hormone, and growth factors. Agents being investigated for treatment of ulcerative colitis include many of those mentioned above. Controlled clinical trials are currently being conducted, exploring the safety and efficacy of old and new biologic agents, and the search certainly will open new and exciting perspective on the development of therapies for inflammatory bowel disease. A review is made of the main areas of research exploring the mechanisms associated with the pathogenesis of IBD, providing advances in the agents currently in use, and identifying a host of new therapeutic biologic targets.
PMID: 19707398 [PubMed - in process]
________________________________________NEURONAL AUTOIMMUNE DISORDERS_____________________________________
J Neurol. 2009 Dec 25. [Epub ahead of print]
Antibodies and neuronal autoimmune disorders of the CNS.
Graus F, Saiz A, Dalmau J.Servei de Neurologia, Hospital Clinic, Institut d' Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Villarroel 170, 08036, Barcelona, Spain, We review the neuronal antibodies described in CNS disorders in order to clarify their diagnostic value, emphasize potentials pitfalls and limitations in the diagnosis of paraneoplastic neurological syndromes (PNS), and examine the current evidence for a possible pathogenic role. We propose to classify the neuronal antibodies associated with syndromes resulting from CNS neuronal dysfunction into two groups according to the location of the antigen: inside the neuron or in the cell membrane. Group I includes antibodies which target intracellular antigens and probably are not pathogenic. They are further subdivided into three groups. Group Ia comprises well-characterized onconeural antibodies (Hu (ANNA1), Yo (PCA1), Ri (ANNA2), CV2 (CRMP5), amphiphysin, Ma2) that are useful for the diagnosis of PNS. Group Ib antibodies (SOX and ZIC) are cancer-specific but there is no evidence that the immune response is in any way pathogenically related to the PNS. Antibodies in group Ic (glutamic acid decarboxylase (GAD), adenylate kinase 5 and Homer 3) identify non-PNS: stiff-person syndrome (SPS), cerebellar ataxia, and limbic encephalitis (LE). Group II antibodies recognize neuronal surface antigens. Antibodies in group IIa associate with characteristic CNS syndromes but their detection does not indicate that the disorder is paraneoplastic. Antibodies to potassium channels, AMPA and GABA(B) receptors are associated with LE, NMDA receptor antibodies identify a well-defined encephalitis, and antibodies against glycine receptors associate with SPS with encephalitis. A pathogenic role of the antibodies is suggested by the response of symptoms to immunotherapy and the correlation between antibody titers and neurological outcome. Lastly, Group IIb includes antibodies that are found in patients with paraneoplastic cerebellar ataxia associated with lung cancer (P/Q type calcium channels antibodies) or Hodgkin disease (metabotropic glutamate receptor type 1 antibodies).PMID: 20035430 [PubMed - as supplied by publisher]


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______________________________________________________Environmental Toxins and Thyroid cancer and autoimmune disease_____________
Altern Med Rev. 2009 Dec;14(4):326-46.
Thyroid disruption: mechanism and clinical implications in human health. Patrick L. Bastyr University graduate 1984; private practice, Durango, CO, specializing in environmental medicine and chronic hepatitis C; faculty of the Postgraduate Certification Course in Environmental Medicine, Southwest College of Naturopathic Medicine; contributing editor, Alternative Medicine Review. Correspondence address: Durango Natural Medicine 117 CR 250 Suite A, Durango, CO 81301 Exposure to specific environmental toxins, including polychlorinated biphenyls, dioxins, phthalates, polybrominated diphenyl ethers (PBDEs), and other halogenated organochlorines, has been shown to interfere with the production, transportation, and metabolism of thyroid hormones by a variety of mechanisms. A broad range of chemicals, with structural similarity to thyroid hormone, have been shown to bind to thyroid receptors with both agonist and antagonist effects on thyroid hormone signaling. The incidence of thyroid disease in the United States, particularly for thyroid cancer and thyroid autoimmune disease, is increasing substantially. The evidence for the significant effects of background levels of thyroid-disrupting chemicals, the known pathways for thyroid disruptors, and the evidence and implications for neurodevelopmental damage due to thyroid-disrupting chemicals is reviewed.PMID: 20030460 [PubMed - in process]

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_____________FIBROMYALGIA AND Autonomic nervous system and neuroendocrinocrine response_______________________________
Am J Med. 2009 Dec;122(12 Suppl):S22-30.
Pathophysiology of fibromyalgia.
Bradley LA.Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. This article reviews the biologic, genetic, and environmental factors that may contribute to the pathophysiology of fibromyalgia. As an affective spectrum disorder, fibromyalgia may share these causal factors with a number of related and co-occurring pain conditions, such as irritable bowel syndrome or temporomandibular disorder. There is strong evidence that cardinal pain symptoms of fibromyalgia may be due to alterations in central processing of sensory input, along with aberrations in the endogenous inhibition of pain. Genetic research has shown familial aggregation of fibromyalgia and other related disorders such as major depressive disorder. Exposure to physical or psychosocial stressors, as well as abnormal biologic responses in the autonomic nervous system and neuroendocrine responses, may also contribute to dysfunctional pain processing. As fibromyalgia research continues to progress, it is expected that the pathophysiology of this disorder will be further elucidated, leading to more rational and targeted strategies for the treatment of patients with this condition. (c)
2009 Elsevier Inc.
PMID: 19962493 [PubMed - in process]

_______________ENVIRONMENTAL EXPOSURES AND MALE FERTILITY_______________________________________________
Int J Occup Med Environ Health. 2010 Jan 6:1-25. [Epub ahead of print]
Environmental factors and semen quality. Jurewicz J, Hanke W, Radwan M, Bonde JP.Department of Environmental Epidemiology, Nofer Institute of Occupational Medicine, £ódŸ, Poland.
Objectives: An increasing number of reports suggest that chemical and physical agents in the environment, introduced and spread by human activity, may affect male fertility in humans. This article aims at evaluating the impact of environmental exposures (pesticides, phthalates, PCBs, air pollution, trihalomethanes (THMs), mobile phones) on semen quality, by reviewing most recent published literature. Materials and Methods: Epidemiological studies focusing on exposure to environmental factors and semen quality for the last ten years were identified by a search of the Pubmed, Medline, Ebsco, Agricola and Toxnet literature bases. Results: The results from the presented studies suggest that there are strong and rather consistent indications that some pesticides besides DBCP (e.g. DDT/Dichlorodiphenyldichloroethylene [DDE], ethylenedibromide, organophosphates) affects sperm count. PCBs are detrimental to sperm motility. In case of air pollution, studies suggest a link between ambient air pollutants and various semen characteristics. Additional research is needed to corroborate this association and to establish the causal agents. Results of few studies on subfertile men demonstrate associations between phthalate levels commonly experienced by the public and impaired sperm quality (impact on sperm concentration, morphology, motility), but the findings have not been corroborated in studies of men from the general population. Mobile phones might adversely affect the quality of semen by decreasing mostly motility but also the sperm counts, viability and morphology. In spite of their consistent results, most of the studies are rather small. Association between exposure to THMs and poor semen quality was not observed. Conclusions: Epidemiological studies suggest awareness of environmental factors which may affect semen quality. In case both of well proven and disputable reproductive and developmental hazards, it is necessary to prevent parental exposure to the agents associated with those hazards.PMID: 20053623 [PubMed - as supplied by publisher]

_______________SARCODOSIS AND WTC RESCUE WORKERS_____________________________________________________________________
J Clin Rheumatol. 2010 Jan;16(1):26-7.
Sarcoidosis in world trade center rescue workers presenting with rheumatologic manifestations.
Bowers B, Hasni S, Gruber BL.Department of Medicine, New York College of Osteopathic Medicine, Old Westbury, NY 11568, USA. The health consequences of the World Trade Center collapse are unknown, but likely to be significant and may take years to fully appreciate. Sarcoidosis is a multisystem inflammatory disorder of unknown etiology characterized pathologically by noncaseating granulomas. Inciting events, such as infectious agents or possible environmental exposures, have been postulated as the source of antigen exposure initiating an inflammatory cascade. We describe 2 cases of sarcoidosis in rescue workers with significant exposure from the World Trade Center collapse, who presented with extrapulmonary rheumatologic manifestations. Our first case involved a 33-year-old white New York City man detective found to have sarcoidosis following an evaluation of diffuse joint pain. The second case involved a 40-year-old African American man, New York City officer, who presented with uveitis, and was subsequently diagnosed with sarcoidosis. These 2 cases extend the spectrum of disorders resulting from the World Trade Center disaster and illustrate the need for clinicians to be aware of the diverse presentations of sarcoidosis in this patient population.PMID: 20051752 [PubMed - in process]

______________________________________MERCURY AND HEALTH CARDIOVASCULAR AND NITRIC OXIDE____________________
Basic Clin Pharmacol Toxicol. 2009 Dec 30. [Epub ahead of print]
Environmental Exposure to Methylmercury is Associated with a Decrease in Nitric Oxide Production.
de Marco KC, Passos CJ, Sertorio J, Tanus-Santos JE, Barbosa F Jr.Department of Clinical, Toxicological and Food Science Analysis, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. Some studies have recently suggested that mercury (Hg)-exposed populations face increased risks of cardiovascular diseases, and experimental data indicate that such risks might be due to reductions in nitric oxide bioavailability. However, no previous study has examined whether Hg exposure affects plasma nitrite concentrations in humans as an indication of nitric oxide production. Here, we investigated whether there is an association between circulating nitrite and Hg concentrations in whole blood, plasma and hair from an exposed methylmercury (MeHg) population. Hair and blood samples were collected from 238 persons exposed to MeHg from fish consumption. Hg concentrations in plasma (PHg), whole blood (BHg) and hair Hg (HHg) were determined by inductively coupled plasma-mass spectrometry. Mean BHg content was 49.8 +/- 35.2 mug/l, mean PHg was 7.8 +/- 6.9 mug/l and HHg 14.6 +/- 10.6 mug/g. Mean plasma nitrite concentration was 253.2 +/- 105.5 nM. No association was found between plasma nitrite concentration and BHg or HHg concentrations in a univariate model. However, multiple regression models adjusted for gender, age and fish consumption showed a significant association between plasma nitrite and plasma Hg concentration (beta = -0.1, p < 0.001). Our findings constitute preliminary clinical evidence that exposure to MeHg may cause inhibitory effects on the production of endothelial nitric oxide.PMID: 20050842 [PubMed - as supplied by publisher]

_____________________ORGANOCHLORINE PESTICIDES AND DOPAMINERGIC NEURONS AND ROLE OF OXIDATIVE STRESS______________________
Neurotoxicology. 2009 Dec 29. [Epub ahead of print]
Organochlorine pesticides dieldrin and lindane induce cooperative toxicity in dopaminergic neurons: Role of oxidative stress.
Sharma H, Zhang P, Barber DS, Liu B.Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA. Elevated environmental exposure to pesticides has been implicated as a contributing factor in the pathogenesis of Parkinson's disease (PD), a progressive movement disorder resulted from degeneration of the nigrostriatal dopaminergic (DA) pathway. Organochlorine pesticides (OCPs) including dieldrin and lindane remain ubiquitous in the environment and food supply due to their resistance to degradation and bioaccumulation along the food chain. While prior studies have gained insight into the neurotoxic effects of individual OCPs such as dieldrin, the effect of combinations of coexisting OCPs is lacking. In this study, we determined the combined effect of dieldrin and lindane on DA neurons and potential mechanism of action. Combinations of dieldrin and lindane (5-25muM) were more effective in causing toxicity in immortalized rat N27 DA neurons than when used alone. Mechanistically, dieldrin and lindane combination induced a rapid increase in the levels of intracellular reactive oxygen species, a decrease in mitochondrial membrane potential and activation of caspase 3/7. Pretreatment with antioxidant N-acetyl cysteine blocked the effect of dieldrin and lindane on ROS generation and mitochondrial membrane potential and protected against dieldrin- and lindane-induced neurotoxicity. These results demonstrate that dieldrin and lindane work cooperatively to induce DA neurotoxicity through the induction of oxidative stress and mitochondrial dysfunction. These findings may advance understanding of the role of pesticides in the multi-factorial etiology of PD. Copyright © 2009. Published by Elsevier B.V.PMID: 20036686 [PubMed - as supplied by publisher

________________ WTC RESPONDERS AND RESPIRATORY HEALTH_____________________________________________________________
Occup Med (Lond). 2009 Dec 24. [Epub ahead of print]
Long-term respiratory symptoms in World Trade Center responders.
Mauer MP, Cummings KR, Hoen R.Bureau of Occupational Health, Center for Environmental Health, New York State Department of Health, Troy, NY, USA.
BACKGROUND: New York State (NYS) employees who responded to the World Trade Center (WTC) disaster on or after 11 September 2001 potentially experienced exposures that might have caused persistent respiratory effects. NYS responders represent a more moderately exposed population than typical first responders. AIMS: To assess whether NYS employees who were WTC responders were more likely than controls to report lower respiratory symptoms (LRS) or a diagnosis of asthma 5 years post-9/11. Persistence and severity of symptoms were also evaluated. METHODS: Participants were initially mailed self-administered questionnaires (initial, Year 1, Year 2) and then completed a telephone interview in Year 3. Data were analysed using Poisson's regression models. RESULTS: WTC exposure was associated with LRS, including cough symptoms suggestive of chronic bronchitis, 5 years post-9/11. When exposure was characterized using an exposure assessment method, the magnitude of effect was greater in those with exposure scores above the mean. WTC exposure was associated with persistence of LRS over the 3 year study period. Results also suggest that participants with the highest exposures were more likely to experience increased severity of their asthma condition and/or LRS. CONCLUSIONS: Our findings suggest that even in a moderately exposed responder population, lower respiratory effects were a persistent problem 5 years post-9/11, indicating that some WTC responders require ongoing monitoring.PMID: 20035001 [PubMed - as supplied by publisher]

_____________CHLORINATED PESTICIDES AND HEALTH________________________________________________________
Altern Med Rev. 2009 Dec;14(4):347-59.
Chlorinated pesticides: threats to health and importance of detection.
Crinnion WJ.1982 graduate of Bastyr University; practice since 1982 with a special focus on treating chronic diseases caused by environmental toxic burden; conducts post-graduate seminars in environmental medicine; professor and Chair of Environmental Medicine, Southwest College of Naturopathic Medicine; contributing editor, Alternative Medicine Review. Although chlorinated pesticides have been mostly banned from use in the United States, their persistent presence in the environment poses an ongoing threat to health. Because of the lipophilic nature of chlorinated pesticides, they are bioaccumulative and difficult to excrete from the body. A select group of these xenobiotics is also associated with a wide range of health problems, identification of which would aid in disease prevention and reversal. Ongoing research by the Centers for Disease Control and Prevention now provides national standards for some of these compounds, allowing the clinician to evaluate levels in a patient. Serum samples are easily obtained and can reveal the presence of these xenobiotics. Eight of the most commonly found and harmful chlorinated pesticides are reviewed in this article, along with the most common sources of exposure and possible action steps.PMID: 20030461 [PubMed - in process]

_____________________________________Environomental toxins organochlorines and thyroid hormones________________________
Altern Med Rev. 2009 Dec;14(4):326-46.
Thyroid disruption: mechanism and clinical implications in human health.
Patrick L. Bastyr University graduate 1984; private practice, Durango, CO, specializing in environmental medicine and chronic hepatitis C; faculty of the Postgraduate Certification Course in Environmental Medicine, Southwest College of Naturopathic Medicine; contributing editor, Alternative Medicine Review. Correspondence address: Durango Natural Medicine 117 CR 250 Suite A, Durango, CO 81301
Exposure to specific environmental toxins, including polychlorinated biphenyls, dioxins, phthalates, polybrominated diphenyl ethers (PBDEs), and other halogenated organochlorines, has been shown to interfere with the production, transportation, and metabolism of thyroid hormones by a variety of mechanisms. A broad range of chemicals, with structural similarity to thyroid hormone, have been shown to bind to thyroid receptors with both agonist and antagonist effects on thyroid hormone signaling. The incidence of thyroid disease in the United States, particularly for thyroid cancer and thyroid autoimmune disease, is increasing substantially. The evidence for the significant effects of background levels of thyroid-disrupting chemicals, the known pathways for thyroid disruptors, and the evidence and implications for neurodevelopmental damage due to thyroid-disrupting chemicals is reviewed.PMID: 20030460 [PubMed - in process]

__________________OXIDATIVE STRESS AND PESTICIDES__________________________________________________________________________
Neuro Endocrinol Lett. 2009 Dec 21;30(Suppl):2-12. [Epub ahead of print]
A review: Oxidative stress in fish induced by pesticides.
Slaninova A, Smutna M, Modra H, Svobodova Z.Department of Veterinary Public Health and Toxicology, Faculty of Veterinary Hygiene and Ecology, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic. The knowledge in oxidative stress in fish has a great importance for environmental and aquatic toxicology. Because oxidative stress is evoked by many chemicals including some pesticides, pro-oxidant factors' action in fish organism can be used to assess specific area pollution or world sea pollution. Hepatotoxic effect of DDT may be related with lipid peroxidation. Releasing of reactive oxygen species (ROS) after HCB exposure can be realized via two ways: via the uncoupling of the electron transport chain from monooxygenase activity and via metabolism of HCB major metabolite pentachlorophenol. Chlorothalonil disrupts mitochondrial metabolism due to the impairment of NADPH oxidase function. Activation of spleen macrophages and a decrease of catalase (CAT) activity have been observed after endosulfan exposure. Excessive release of superoxide radicals after etoxazole exposure can cause a decrease of CAT activity and increase phagocytic activity of splenocytes. Anticholinergic activity of organophosphates leads to the accumulation of ROS and resulting lipid peroxidation. Carbaryl induces changes in the content of glutathione and antioxidant enzymes activities. The antioxidant enzymes changes have been observed after actuation of pesticides deltamethrin and cypermethrin. Bipyridyl herbicides are able to form redox cycles and thereby cause oxidative stress. Low concentrations of simazine do not cause oxidative stress in carps during sub-chronic tests while sublethal concentrations of atrazin can induce oxidative stress in bluegill sunfish. Butachlor causes increased activity of superoxide dismutase -catalase system in the kidney. Rotenon can inhibit the electron transport in mitochondria and thereby increase ROS production. Dichloroaniline, the metabolite of diuron, has oxidative effects. Oxidative damage from fenpyroximate actuation is related to the disruption of mitochondrial redox respiratory chain. Low concentration of glyphosate can cause mild oxidative stress.PMID: 20027135 [PubMed - as supplied by publisher]

___________________DEPLETED URANIUM RESEARCH ABSTRACT________________________________________________
Chem Res Toxicol.. [Epub ahead of print]
Depleted Uranium Induces Neoplastic Transformation in Human Lung Epithelial Cells.
Xie H, Lacerte C, Thompson WD, Wise JP.Wise Laboratory of Environmental and Genetic Toxicology, Maine Center for Toxicology and Environmental Health, and Department of Applied Medical Sciences, University of Southern Maine, 96 Falmouth Street, P.O. Box 9300, Portland, Maine 04104-9300.
Depleted uranium (DU) is commonly used in military armor and munitions, and thus, exposure of soldiers and noncombatants is frequent and widespread. Previous studies have shown that DU has both chemical and radiological toxicity and that the primary route of exposure of DU to humans is through inhalation and ingestion. However, there is limited research information on the potential carcinogenicity of DU in human bronchial cells. Accordingly, we determined the neoplastic transforming ability of particulate DU to human bronchial epithelial cells (BEP2D). We observed the loss of contact inhibition and anchorage independent growth in cells exposed to DU after 24 h. We also characterized these DU-induced transformed cell lines and found that 40% of the cell lines exhibit alterations in plating efficiency and no significant changes in the cytotoxic response to DU. Cytogenetic analyses showed that 53% of the DU-transformed cell lines possess a hypodiploid phenotype. These data indicate that human bronchial cells are transformed by DU and exhibit significant chromosome instability consistent with a neoplastic phenotype.PMID: 20000475 [PubMed - as supplied by publisher]

___________________DEPLETED URANIUM RESEARCH ABSTRACT________________________________________________

J Radiat Res (Tokyo). 2009 Nov;50(6):521-8. Epub 2009 Oct 3.
A study assessing the genotoxicity in rats after chronic oral exposure to a low dose of depleted uranium.
Hao Y, Li R, Leng Y, Ren J, Liu J, Ai G, Xu H, Su Y, Cheng T.State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, College of Preventive Medicine, Third Military Medical University, Chongqing, China.
PURPOSE: The aim of this study was to evaluate the potential genotoxicity induced by chronic oral exposure to depleted uranium (DU). MATERIALS AND METHODS: Weanling Wistar rats (F(0)), 50/sex/group, were exposed to DU in food at doses of 0, 4, or 40 mg kg(-1)day(-1) for four months. They were subsequently mated, resulting in the birth of F(1) rats. Fifty F(l) weanlings/sex/group were exposed for four months to the same dose levels as their parents. After four months, the uranium content in the tissues, the potential damage to the genetic material, and pathomorphological changes of the testicles were observed in both F(0) and F(1) rats. The genotoxicity of DU was evaluated by the following methods: sperm abnormality assessment, the bone-marrow micronucleus test, and the comet assay. RESULTS: Uranium content in F(1) rats was significantly higher than that in F(0) rats in both the kidney and ovary (p < 0.05). The sperm abnormality rate, marrow cell micronuclei rate, comet tail length, and tailed cell percentage increased in each treatment group in each generation compared with the control group (p < 0.05). When comparing F(1) with F(0) rats, significant differences were detected for most of the indicators, with F(1) rats always exhibiting more damage (p < 0.05). With regard to pathomorphological changes in the testicles, the sperm displayed atypical changes, including thickening of the anachromasis nucleolus, which seemed to be more severe in F(1) rats. CONCLUSION: Genotoxicity may be induced in rats after chronic oral exposure to a low dose of DU.PMID: 19801891 [PubMed - in process]

_______________________ORGANOPHOSPHATE RESEARCH ABSTRACT(PESTICIDES < SARIN----Parkinson's______________________________________________
Epidemiology. 2010 Jan;21(1):87-94.
Paraoxonase 1, agricultural organophosphate exposure, and Parkinson disease.
Manthripragada AD, Costello S, Cockburn MG, Bronstein JM, Ritz B.Department of Epidemiology, UCLA School of Public Health, Los Angeles, CA 90095, USA.
BACKGROUND: Human, animal and cell models support a role for pesticides in the etiology of Parkinson disease. Susceptibility to pesticides may be modified by genetic variants of xenobiotic enzymes, such as paraoxonase, that play a role in metabolizing some organophosphates. METHODS: We examined associations between Parkinson disease and the organophosphates diazinon, chlorpyrifos, and parathion, and the influence of a functional polymorphism at position 55 in the coding region of the PON1 gene (PON1-55). From 1 January 2001 through 1 January 2008, we recruited 351 incident cases and 363 controls from 3 rural California counties in a population-based case-control study. Participants provided a DNA sample, and residential exposure to organophosphates was determined from pesticide usage reports and a geographic information system (GIS) approach. We assessed the main effects of both genes and pesticides in unconditional logistic regression analyses, and evaluated the effect of carrying a PON1-55 MM variant on estimates of effects for diazinon, chlorpyrifos, and parathion exposures. RESULTS: Carriers of the variant MM PON1-55 genotype exposed to organophosphates exhibited a greater than 2-fold increase in Parkinson disease risk compared with persons who had the wildtype or heterozygous genotype and no exposure (for diazinon, odds ratio = 2.2 [95% confidence interval = 1.1-4.5]; for chlorpyrifos, 2.6 [1.3-5.4]). The effect estimate for chlorpyrifos, was more pronounced in younger-onset cases and controls (<or=60 years) (5.3 [1.7-16]). No increase in risk was noted for parathion. CONCLUSION: The increase in risk we observed among PON1-55 variant carriers for specific organophosphates metabolized by PON1 underscores the importance of considering susceptibility factors when studying environmental exposures in Parkinson disease.
PMID: 19907334 [PubMed - in process]

_______________________ORGANOPHOSPHATE RESEARCH ABSTRACT(PESTICIDES < SARIN______________________________________________
Toxicol Appl Pharmacol. 2009 Nov 13. [Epub ahead of print]
Association between organophosphate pesticides exposure and thyroid hormones in floriculture workers.
Lacasaña M, López-Flores I, Rodríguez-Barranco M, Aguilar-Garduño C, Blanco-Muñoz J, Pérez-Méndez O, Gamboa R, Bassol S, Cebrian ME.Escuela Andaluza de Salud Pública, Granada, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), Spain. The ability of organophosphate pesticides to disturb thyroid gland function has been demonstrated by experimental studies on animal, but evidence of such effects on human remains scarce. The aim of this study was to assess the association between exposure to organophosphate compounds and serum levels of thyroid hormones in floriculture workers. A longitudinal study was conducted on 136 male subjects from the State of Mexico and Morelos, Mexico, occupationally exposed to organophosphate pesticides, during agricultural periods of high (rainy season) and low (dry season) levels of pesticide application. Using a structured questionnaire, a survey was carried out on sociodemographic characteristics, anthropometry, clinical history, alcohol and tobacco consumption, residential chemical exposure, and occupational history. Urine and blood samples were taken the day after pesticide application to determine urine dialkylphosphate (DAP) levels, serum levels of TSH, total T(3), total T(4), serum PON1 activity, and serum p,p'-DEE levels. The analysis of the association between DAP levels and thyroid hormonal profile was carried out using multivariate generalized estimating equation (GEE) models. Our results showed an increase in both TSH and T(4) hormones in serum associated with a increase in total dimethylphosphate levels (SigmaDMP) in urine (p-trend<0.001) and a decrease in total T(3) serum levels with an increase of SigmaDMP levels in the urine (p-trend=0.053). These results suggest that exposure to organophosphate pesticides may be responsible of increasing TSH and T(4) serum hormone levels and decreasing T(3) serum hormone levels, therefore supporting the hypothesis that organophosphate pesticides act as endocrine disruptors in humans.
PMID: 19914268 [PubMed - as supplied by publisher]

_______________________ORGANOPHOSPHATE RESEARCH ABSTRACT(PESTICIDES < SARIN______________________________________________
Biomarkers. 2009 Nov;14(7):443-51.
DNA damage in horticultural farmers: a pilot study showing an association with organophosphate pesticide exposure. Atherton KM, Williams FM, Egea González FJ, Glass R, Rushton S, Blain PG, Mutch E.Institute for Research on Environment and Sustainability, Newcastle University, Newcastle upon Tyne, UK.
A study of horticultural farmers exposed to organophosphate pesticides (OPs) and controls investigated the relationships between OP exposure, DNA damage and oxidative stress. Blood acetylcholinesterase (AChE) and urinary dialkylphosphate (DAP) levels determined exposure and 8-hydroxy-29- deoxyguanosine (8OHdG) indicated oxidative stress status. The farmers had approximately 30% lower AChE activity and increased DAP levels compared with the controls, reflecting moderate OP exposure. They had higher DNA damage than the controls and there was a significant positive relationship between DAP and DNA damage with greater than 95% power. The farmers also had a significant positive relationship between urinary DAP and 8OHdG levels.PMID: 19863182 [PubMed - in process]

_______________________ORGANOPHOSPHATE RESEARCH ABSTRACT(PESTICIDES < SARIN______________________________________________
J Occup Health. 2009;51(6):488-97. Epub 2009 Oct 23.
Chronic exposures to cholinesterase-inhibiting pesticides adversely affect respiratory health of agricultural workers in India.
Chakraborty S, Mukherjee S, Roychoudhury S, Siddique S, Lahiri T, Ray MR.Department of Experimental Hematology, Chittaranjan National Cancer Institute, Kolkata 700 026, India.
OBJECTIVE: The impact of long term exposure to cholinesterase (ChE)-inhibiting organophosphate (OP) and carbamate (C) pesticides on the respiratory health of agricultural workers in India was investigated. METHODS: Three hundred and seventy-six nonsmoking agricultural workers (median age 41 yr) from eastern India who sprayed OP and C pesticides in the field and 348 age- and sex-matched control subjects with non-agricultural occupations from the same locality were enrolled. Prevalence of respiratory symptoms was obtained by questionnaire survey, and pulmonary function tests were carried out by spirometry. Chronic obstructive pulmonary disease (COPD) was diagnosed by the Global Obstructive Lung Disease (GOLD) criteria, and erythrocyte acetylcholinesterase (AChE) was measured by the Ellman method. RESULTS: Agricultural workers had greater prevalences of upper and lower respiratory symptoms, and appreciable reduction in spirometric measurements. Overall, lung function reduction was noted in 48.9% of agricultural workers compared with 22.7% of control, and a restrictive type of deficit was predominant. COPD was diagnosed in 10.9% of agricultural workers compared with 3.4% of controls (p<0.05 in chi(2) test), and the severity of the disease was greater in agricultural workers. Red blood cell (RBC) AChE was lowered by 34.2% in agricultural workers, and the fall in AChE level was positively associated with respiratory symptoms, lung function decrement and COPD after controlling for education and income as potential confounders. CONCLUSIONS: Long-term exposure to cholinesterase-inhibiting agricultural pesticides currently in use in India is associated with a reduction in lung function, COPD and a rise in respiratory symptoms.PMID: 19851039 [PubMed - in process]

_______________________ORGANOPHOSPHATE RESEARCH ABSTRACT(PESTICIDES < SARIN______________________________________________
Occup Environ Med. 2009 Oct 9. [Epub ahead of print]
Occupational determinants of serum cholinesterase inhibition among organophosphate-exposed agricultural pesticide handlers in Washington State.
Hofmann JN, Keifer MC, De Roos AJ, Fenske RA, Furlong CE, van Belle G, Checkoway H.University of Washington, United States.
OBJECTIVE: To identify potential risk factors for serum cholinesterase (BuChE) inhibition among agricultural pesticide handlers exposed to organophosphate (OP) and N-methyl-carbamate (CB) insecticides. METHODS: We conducted a longitudinal study among 154 agricultural pesticide handlers who participated in the Washington State cholinesterase monitoring program in 2006 and 2007. BuChE inhibition was analyzed in relation to reported exposures before and after adjustment for potential confounders using linear regression. Odds ratios estimating the risk of 'BuChE depression' (>20% from baseline) were also calculated for selected exposures based on unconditional logistic regression analyses. RESULTS: An overall decrease in mean BuChE activity was observed among study participants at the time of follow-up testing during the OP/CB spray season relative to pre-season baseline levels (mean decrease of 5.6%, P < 0.001). Score for estimated cumulative exposure to OP/CB insecticides in the past 30 days was a significant predictor of BuChE inhibition (coefficient = -1.74, P < 0.001). Several specific work practices and workplace conditions were associated with greater BuChE inhibition, including mixing/loading pesticides and cleaning spray equipment. Factors that were protective against BuChE inhibition included full-face respirator use, wearing chemical-resistant boots, and storing personal protective equipment in a locker at work. CONCLUSIONS: Despite existing regulations, agricultural pesticide handlers continue to be exposed to OP/CB insecticides at levels resulting in BuChE inhibition. These findings suggest that modifying certain work practices could potentially reduce BuChE inhibition. Replication from other studies will be valuable.
PMID: 19819864 [PubMed - as supplied by publisher]

_______________________ORGANOPHOSPHATE RESEARCH ABSTRACT(PESTICIDES < SARIN______________________________________________
Biomarkers. 2009 Aug 18. [Epub ahead of print]
DNA damage in horticultural farmers: a pilot study showing an association with organophosphate pesticide exposure.
Atherton KM, Williams FM, González FJ, Glass R, Rushton S, Blain PG, Mutch E.Institute for Research on Environment and Sustainability, Newcastle University, Newcastle upon Tyne, UK. A study of horticultural farmers exposed to organophosphate pesticides (OPs) and controls investigated the relationships between OP exposure,DNA damage and oxidative stress. Blood acetylcholinesterase (AChE) and urinary dialkylphosphate (DAP) levels determined exposure and 8-hydroxy-29- deoxyguanosine (8OHdG) indicated oxidative stress status. The farmers had approximately 30% lower AChE activity and increased DAP levels compared with the controls, reflecting moderate OP exposure. They had higher DNA damage than the controls and there was a significant positive relationship between DAP and DNA damage with greater than 95% power. The farmers also had a significant positive relationship between urinary DAP and 8OHdG levels.PMID: 19686088 [PubMed - as supplied by publisher]

_______________________ORGANOPHOSPHATE RESEARCH ABSTRACT(PESTICIDES < SARIN______________________________________________
Clin Neurophysiol. 2009 Sep;120(9):1693-8. Epub 2009 Aug 14.
Auditory event-related potential changes in chronic occupational exposure to organophosphate pesticides.
Dassanayake T, Gawarammana IB, Weerasinghe V, Dissanayake PS, Pragaash S, Dawson A, Senanayake N.Department of Physiology, Faculty of Medicine, University of Peradeniya, Peradeniya 20400, Sri Lanka.
OBJECTIVE: To determine whether chronic occupational exposure to organophosphates (OP) pesticides leads to cognitive impairment using event-related potentials (ERPs). METHODS: ERPs of 38 vegetable farmers applying OP pesticides and 35 controls were recorded using an auditory oddball paradigm. The N1, P2, N2 and P300 ERP components and the number of counting errors were compared between the groups. RESULTS: The farmers made significantly more counting errors than controls in the oddball task. The mixed model ANOVA of component latencies revealed a significant componentxgroup interaction, suggesting farmers had a greater delay in later ERP components. Intergroup comparisons of individual components showed significant delays in N2 and P300 latencies. Subsequent ANCOVA showed significant P300 delay even after adjusting for the latency of the preceding component, N2. Intergroup differences of P300 amplitudes were not significant, although there was limited evidence of a difference in scalp topography. CONCLUSION: Our findings indicate that chronic low-level occupational exposure to OP pesticides is associated with progressively increasing delay in successive ERP components, particularly P300. SIGNIFICANCE: Chronic exposure to OP pesticides may delay the neurophysiological processes underlying early stages of selective attention and late stages of sensory information processing that include stimulus evaluation and updating of working memory.PMID: 19683468 [PubMed - indexed for MEDLINE]

______________ GULF WAR ILNESS PYRIDOSTIGMINE BROMIDE P TABS RESEARCH ABSTRACT_____________________________
Behav Brain Res. 2009 Nov 5;203(2):207-14. Epub 2009 May 9.
Gulf War illness: Effects of repeated stress and pyridostigmine treatment on blood-brain barrier permeability and cholinesterase activity in rat brain. Amourette C, Lamproglou I, Barbier L, Fauquette W, Zoppe A, Viret R, Diserbo M.Département de Radiobiologie et Radiopathologie, Centre de Recherches Emile Pardé 24, Avenue des maquis du Grésivaudan, BP87 - 38702 La Tronche Cedex, France. After the first Persian Gulf War, many soldiers have complained of a variety of symptoms designated as "Gulf War Illness". Among several factors, implication of pyridostigmine (PB) in late cognitive dysfunction is highly likely. As a hypothesis to explain these behavioural disorders is a potentiation of the operational stress effects by pyridostigmine. We have previously described that repeated stress combined to pyridostigmine treatment induces learning dysfunction linked to genomic cerebral modifications [Barbier L, Diserbo M, Lamproglou I, Amourette C, Peinnequin A, Fauquette W. Repeated stress in combination with pyridostigmine: part II-changes in selected cerebral genes expression. Behav Brain Res 2009;197:292-300; Lamproglou I, Barbier L, Diserbo M, Fauvelle F, Fauquette W, Amourette C. Repeated stress in combination with pyridostigmine: part I-long-term behavioural consequences. Behav Brain Res 2009;197:301-10]. In the present study, using the same experimentalmodel, we attempted to determine if such modifications are linked to a central passage of pyridostigmine under stress. Indeed it is known that exposure to stress can disrupt blood-brain barrier (BBB) and thereby increase the neurotoxicity induced by chemicals in many cerebral areas. Adult rats were subjected to repeated stress based on a modification of the pole climbing avoidance technique and treated daily by PB (1.5mg/kg/day, oral in water), for two 5-day periods separated by 2-day rest.Just after the last stress session, (3)H-pyridostigmine was administered as a tracer to evaluate BBB breakdown. In brain micro-punches and brain coronal cryosections, we failed to detect any radioactivity in animals chronically stressed and treated by pyridostigmine. Accordingly, no change of ChE activity was noted in any brain area studied. It thus appears that, in our experimental model, pyridostigmine induces effects on central nervous system, but these effects do not seem to be mediated by a central passage of pyridostigmine linked to a BBB opening under stress. These results suggest that pyridostigmine may have central effects, under stress, via indirect mechanisms emerging from a peripheral pathway.
PMID: 19433115 [PubMed - indexed for MEDLINE]

______________________Fibromyalgia ABSTRACTS____________________________________________
Am J Med. 2009 Dec;122(12 Suppl):S44-55.
Further strategies for treating fibromyalgia: the role of serotonin and norepinephrine reuptake inhibitors.
Mease PJ.Seattle Rheumatology Associates, Swedish Medical Center, Seattle, Washington, USA.
Fibromyalgia and associated conditions such as irritable bowel syndrome and temporomandibular disorder involve dysfunctions in central sensitization and pain modulation. Central nervous system dysfunction may also contribute to other symptoms characteristic of fibromyalgia, such as fatigue and sleep disturbance. Two key neurotransmitters in the pain modulation pathway are serotonin and norepinephrine. Preclinical studies using animal models of chronic pain have shown that pharmacologic agents that combine serotonergic and noradrenergic reuptake inhibition, thus augmenting the function of these neurotransmitters, have stronger analgesic effects than agents that inhibit reuptake of either neurotransmitter alone. Although tricyclic antidepressants (TCAs) inhibit reuptake of both serotonin and norepinephrine and have shown efficacy for the treatment of fibromyalgia, long-term use of these drugs is limited owing to poor tolerability. Unlike TCAs, the newer dual reuptake inhibitors of serotonin and norepinephrine, such as the drugs approved by the US Food and Drug Administration (FDA) for fibromyalgia, milnacipran and duloxetine, do not possess significant affinity for other neurotransmitter systems, resulting in diminished side effects and enhanced tolerability. Both duloxetine and milnacipran have shown efficacy in clinical trials by improving pain and other symptoms associated with fibromyalgia. Both compounds inhibit the serotonin and norepinephrine transporters; however, there is a difference in their affinities and selectivity for these transporters. Although duloxetine has affinity for both receptors, it is somewhat more selective for the serotonin transporter. In contrast, milnacipran is somewhat more selective for norepinephrine than serotonin reuptake inhibition. Pharmacologic agents that specifically target serotonin and norepinephrine reuptake may prove to be valuable tools in the treatment of fibromyalgia. (c) 2009 Elsevier Inc.

________________FIBROMYALGIA ABSTRACT RESEARCH______________________________________________
PLoS One. 2009 Dec 30;4(12):e8480.
Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels.
Feng J, Zhang Z, Li W, Shen X, Song W, Yang C, Chang F, Longmate J, Marek C, St Amand RP, Krontiris TG, Shively JE, Sommer SS.Division of Molecular Genetics, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
BACKGROUND: Fibromyalgia syndrome (FMS), a common, chronic, widespread musculoskeletal pain disorder found in 2% of the general population and with a preponderance of 85% in females, has both genetic and environmental contributions. Patients and their parents have high plasma levels of the chemokines MCP-1 and eotaxin, providing evidence for both a genetic and an immunological/inflammatory origin for the syndrome (Zhang et al., 2008, Exp. Biol. Med. 233: 1171-1180). METHODS AND FINDINGS: In a search for a candidate gene affecting inflammatory pathways, among five screened in our patient samples (100 probands with FMS and their parents), we found 10 rare and one common alleles for MEFV, a gene in which various compound heterozygous mutations lead to Familial Mediterranean Fever (FMF). A total of 2.63 megabases of genomic sequence of the MEFV gene were scanned by direct sequencing. The collection of rare missense mutations (all heterozygotes and tested in the aggregate) had a significant elevated frequency of transmission to affecteds (p = 0.0085, one-sided exact binomial test). Our data provide evidence that rare missense variants of the MEFV gene are, collectively, associated with risk of FMS and are present in a subset of 15% of FMS patients. This subset had, on average, high levels of plasma IL-1beta (p = 0.019) compared to FMS patients without rare variants, unaffected family members with or without rare variants, and unrelated controls of unknown genotype. IL-1beta is a cytokine associated with the function of the MEFV gene and thought to be responsible for its symptoms of fever and muscle aches. CONCLUSIONS: Since misregulation of IL-1beta expression has been predicted for patients with mutations in the MEFV gene, we conclude that patients heterozygous for rare missense variants of this gene may be predisposed to FMS, possibly triggered by environmental factors.PMID: 20041150 [PubMed - in process]

_______________________CHRONIC FATIGUE RESEARCH ABSTRACT______________________________________________________________________
Neuro Endocrinol Lett. 2009 Dec 30;30(6). [Epub ahead of print]
Increased 8-hydroxy-deoxyguanosine, a marker of oxidative damage to DNA, in major depression and myalgic encephalomyelitis / chronic fatigue syndrome. Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E.Maes Clinics, Antwerp, Belgium. There is now evidence that major depression and myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) are accompanied by partially overlapping pathophysiological mechanisms, i.e. activation of various inflammatory and oxidative & nitrosative (IO&NS) pathways. The aim of the present study was to examine the urinary excretion of 8-hydroxy-deoxyguanosine (8-OhdG), a marker of oxidative damage to DNA, in depression; ME/CFS; and depression and ME/CFS. Toward this end, morning urine was sampled for the assays of 8-OHdG and creatinine, in 44 patients with ME/CFS; 25 with major depression; 23 with depression and ME/CFS; and 17 normal controls. Severity of fatigue and somatic symptoms was measured by means of the Fibromyalgia and CFS Rating (FF) scale. We found that 49.0% of the variance in the urinary excretion of 8-OHdG was predicted by the regression on creatinine. Consequently, the urinary 8-OHdG excretion should be expressed as the residualized 8-OHdG values after partialling out the effects of creatinine and not by computing the 8-OHdG / creatinine ratio. We found that the residualized urinary excretion of 8-OHdG (adjusted for creatinine) was significantly higher in patients with depression and ME/CFS than in normal controls and all other patients. In the patient group, there were significant correlations between the urinary 8-OHdG and the total score on the FF scale and sadness and flu-like malaise. The findings show increased oxidatively generated DNA damage in patients with major depression and ME/CFS and, therefore, further extent the role played by IO&NS pathways in the pathophysiology of both disorders. Since oxidatively damage to DNA is a risk factor for atherosclerosis and neurodegeneration, our results also explain previous findings on increased cardiovascular morbidity in depression and ME/CFS, and neurodegenerative processes in depression.PMID: 20035260 [PubMed - as supplied by publisher]

_____________________FIBROMYALGIA REVIEW ABSTRACTS________________________________________
Drugs. 2010;70(1):1-14. doi: 10.2165/11530950-000000000-00000.
Pharmacological treatment of fibromyalgia syndrome: new developments.
Staud R.Department of Medicine, University of Florida, College of Medicine, Gainesville, Florida 32610-0221, USA. Fibromyalgia is a chronic pain disorder characterized by widespread pain, stiffness, insomnia, fatigue and distress. Several randomized controlled trials (RCTs) have shown moderate effectiveness of pharmacological therapies for fibromyalgia pain. Evidence from these trials suggests that pharmacological therapy can not only improve pain but also fatigue, function and well-being in patients with fibromyalgia. Duloxetine and milnacipran, two highly selective serotonin-norepinephrine (noradrenaline) reuptake inhibitors, and the alpha(2)delta agonist pregabalin have been approved by the US FDA for the treatment of fibromyalgia symptoms. In general, about half of all treated patients seem to experience a 30% reduction of symptoms, suggesting that many patients with fibromyalgia will require additional therapies. Thus, other forms of treatment, including exercise, cognitive behavioural therapies and self-management strategies, may be necessary to achieve satisfactory treatment outcomes. Despite promising results of pilot trials, RCTs with dopamine receptor agonists and sodium channel antagonists have so far been disappointing for patients with fibromyalgia. However, new pharmacological approaches for the treatment of fibromyalgia pain and insomnia using sodium oxybate appear to be promising.PMID: 20030422 [PubMed - in process]
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Drugs. 2010;70(1):99-108. doi: 10.2165/11202810-000000000-00000.Milnacipran: in fibromyalgia.
Chwieduk CM, McCormack PL.Adis, a Wolters Kluwer Business, Auckland, New Zealand.
Milnacipran is an orally administered selective serotonin and norepinephrine (noradrenaline) reuptake inhibitor indicated for the management of fibromyalgia in adults. In adults, milnacipran was generally effective in the treatment of fibromyalgia in four well designed trials of 3 or 6 months' duration. Composite responder rates for the treatment of fibromyalgia and fibromyalgia pain (co-primary efficacy variables) were generally higher with milnacipran 100 or 200 mg/day (in two divided doses) than with placebo after 12 weeks of fixed-dose treatment. In one study, the composite responder rate for fibromyalgia pain (co-primary efficacy variable) was also higher with milnacipran 200 mg/day than with placebo after 24 weeks of fixed-dose treatment. Furthermore, the benefits of milnacipran therapy were sustained in a 6-month extension of an initial double-blind trial. Improvements from baseline in mean 24-hour recall pain scores, mean weekly recall pain scores, Patient Global Impression of Change scores and in several items of the Fibromyalgia Impact Questionnaire were observed in patients receiving continuous milnacipran for up to 12 months, as well as in patients who switched from placebo to milnacipran therapy at the start of the extension phase. Milnacipran was generally well tolerated in adults with fibromyalgia, with most adverse events being mild to moderate in severity. Nausea was the most common adverse event reported in milnacipran recipients.PMID: 20030428 [PubMed - in process]
Sleep Med. 2009 Dec 14. [Epub ahead of print]
Impaired sleep quality in fibromyalgia: Detection and quantification with ECG-based cardiopulmonary coupling spectrograms.
Thomas RJ, Mietus JE, Peng CK, Goldberger AL, Crofford LJ, Chervin RD.Division of Pulmonary, Critical Care & Sleep, Department of Medicine, Beth Israel Deaconess Medical Center & Harvard Medical School, 100 Stanley Road, Boston, MA 02468, United States.PMID: 20015685 [PubMed - as supplied by publisher]
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Anesth Analg.. [Epub ahead of print]
The Effects of Nabilone on Sleep in Fibromyalgia: Results of a Randomized Controlled Trial.
Ware MA, Fitzcharles MA, Joseph L, Shir Y.From the *Pain Clinic, McGill University Health Centre;
Background: Sleep disorders affect many patients with chronic pain conditions. Cannabis has been reported by several patient populations to help sleep. We evaluated the safety and efficacy of nabilone, a synthetic cannabinoid, on sleep disturbance in fibromyalgia (FM), a disease characterized by widespread chronic pain and insomnia. Methods: We conducted a randomized, double-blind, active-control, equivalency crossover trial to compare nabilone (0.5-1.0 mg before bedtime) to amitriptyline (10-20 mg before bedtime) in patients with FM with chronic insomnia. Subjects received each drug for 2 wk with a 2-wk washout period. The primary outcome was sleep quality, measured by the Insomnia Severity Index and the Leeds Sleep Evaluation Questionnaire. Secondary outcomes included pain, mood, quality of life, and adverse events (AEs). Results: Thirty-one subjects were enrolled and 29 completed the trial (26 women, mean age 49.5 yr). Although sleep was improved by both amitriptyline and nabilone, nabilone was superior to amitriptyline (Insomnia Severity Index difference = 3.2; 95% confidence interval = 1.2-5.3). Nabilone was marginally better on the restfulness (Leeds Sleep Evaluation Questionnaire difference = 0.5 [0.0-1.0]) but not on wakefulness (difference = 0.3 [-0.2 to 0.8]). No effects on pain, mood, or quality of life were observed. AEs were mostly mild to moderate and were more frequent with nabilone. The most common AEs for nabilone were dizziness, nausea, and dry mouth. Conclusions: Nabilone is effective in improving sleep in patients with FM and is well tolerated. Low-dose nabilone given once daily at bedtime may be considered as an alternative to amitriptyline. Longer trials are needed to determine the duration of effect and to characterize long-term safety.PMID: 20007734 [PubMed - as supplied by publisher]
__________________________________________________
J Bodyw Mov Ther. 2010 Jan;14(1):3-12.
Fascia: A missing link in our understanding of the pathology of fibromyalgia.
Liptan GL.Dept. of Medicine, Oregon Health & Science University, Portland, 97239, United States.
Significant evidence exists for central sensitization in fibromyalgia, however the cause of this process in fibromyalgia-and how it relates to other known abnormalities in fibromyalgia-remains unclear. Central sensitization occurs when persistent nociceptive input leads to increased excitability in the dorsal horn neurons of the spinal cord. In this hyperexcited state, spinal cord neurons produce an enhanced responsiveness to noxious stimulation, and even to formerly innocuous stimulation. No definite evidence of muscle pathology in fibromyalgia has been found. However, there is some evidence for dysfunction of the intramuscular connective tissue, or fascia, in fibromyalgia. This paper proposes that inflammation of the fascia is the source of peripheral nociceptive input that leads to central sensitization in fibromyalgia. The fascial dysfunction is proposed to be due to inadequate growth hormone production and HPA axis dysfunction in fibromyalgia. Fascia is richly innervated, and the major cell of the fascia, the fibroblast, has been shown to secrete pro-inflammatory cytokines, particularly IL-6, in response to strain. Recent biopsy studies using immuno-histochemical staining techniques have found increased levels of collagen and inflammatory mediators in the connective tissue surrounding the muscle cells in fibromyalgia patients. The inflammation of the fascia is similar to that described in conditions such as plantar fasciitis and lateral epicondylitis, and may be better described as a dysfunctional healing response. This may explain why NSAIDs and oral steroids have not been found effective in fibromyalgia. Inflammation and dysfunction of the fascia may lead to central sensitization in fibromyalgia. If this hypothesis is confirmed, it could significantly expand treatment options to include manual therapies directed at the fascia such as Rolfing and myofascial release, and direct further research on the peripheral pathology in fibromyalgia to the fascia.PMID: 20006283 [PubMed - in process]
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Exerc Immunol Rev. 2009;15:42-65.
Exercise in fibromyalgia and related inflammatory disorders: known effects and unknown chances.
Ortega E, García JJ, Bote ME, Martín-Cordero L, Escalante Y, Saavedra JM, Northoff H, Giraldo E.Department of Physiology, Faculty of Sciences, University of Extremadura, Badajoz, Spain.
Fibromyalgia (FM) is characterised by chronic widespread pain and allodynia (pain from stimuli which are not normally painful with pain that may occur other than in the area stimulated) of more than 3 months duration. The current hypothesis of the aetiology of FM includes inflammatory and neuroendocrine disorders. The biophysiology of this syndrome, however; remains still widely elusive, and there are no formally approved therapies. Non-pharmacological interventions in FM patients include habitual exercise programs which improve physical function and quality of life of patients and may even reduce pain. However the mechanisms through which exercise benefits FM symptoms needs to be elucidated. In this article we firstly review the main topics and characteristics of the FM syndrome, while focusing our attention on the inflammatory hypothesis of FM, as well as on the beneficial effects of habitual exercise as a co-therapy for FM patients. In this context, the latest developments in research on anti-inflammatory effects of exercise are also reviewed and discussed. To find out what is known about the connection between benefits of exercise for FM and anti-inflammatory effects of exercise, we carried out a PubMed search using the term "fibromyalgia" and "exercise" together with "inflammation", and no more than ten published articles were found (six of them reviews), which are also discussed. In the second part of the article we present a pilot investigation on a group of 14 female FM patients with a diagnosis of FM by a rheumatologist. They took part in a pool-aquatic program in warm water over a period of fourth months (three weekly 60-min sessions). Circulating inflammatory (IL-1beta, IL-2, IFNgamma, TNFalpha, IL-8, IL-6, IL-4, IL-10 and CRP) and neuroendocrine (NA and cortisol) markers were determined. FM patients showed higher circulating levels of IL-8, IFNgamma and CRP as well as cortisol and NA than age-matched healthy control women. After the exercise program, a significant decrease in IL-8, IFNgamma, and CRP were found, in parallel with a decrease in circulating concentrations of cortisol and increased levels of NA. The results confirm an elevated "inflammatory status" in the FM syndrome and strengthen the hypothesis that the benefits of exercise in FM patients are mediated, at least in part, by its anti-inflammatory effects. A better regulation of the cytokine-HPA axis feedback may be also involved.PMID: 19957871 [PubMed - in process]

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