Gulf War Veterans experiencing Gulf War Illness will not give up in finding answers, help, and treatment modalities for themselves and their fellow veterans. They pledge not to leave their fellow veteran on the field of the war after the war alone. It is indeed time for Buddy Care! As they learn and participate in research and push for effective physiological care.
Gulf War Veterans 1990-91/ Desert Storm Veterans that are suffering from gulf war illness are searching for answers and only through their own continual push to find answers has there been a response at all from their government. Through their efforts a law was passed to get the Veterans Affairs Research Advisory Committee on Gulf War Illness which meets February 28- March 1 in Washington DC. Their efforts have led to the push for research into biomarkers, the best diagnostic tools, and possible treatment modalities for their illnesses. Dr Bach at the Minneapolis Va has been busy examining their blood for clues and has found some clues and has found so far they have a low level chronic coagulation activation problem. Dr Martin Pall in Washington State is working on oxidative stress as a problem in chronic fatigue, gulf war illness and other undiagnosed illnesses. Dr Bach’s research continues and publication of his findings are eagerly awaited. The VA RAC GWI has also reviewed the chronic inflammatory nature of these illnesses at their last meeting in Boston.
The following research studies, highlighted at the end of this article, also focus on tissue factors, coagulation problems that signal medical complications to include cardiovascular problems, strokes, cancer development, and oxidative stress. Gulf War veterans need to be aware of these research findings and share them with their health care providers. Gulf War Veterans are encouraged to be active participants in their care. This means the veterans need to read and digest scientific work which is hard when they have had neurocognitive problems. In this regards, we encourage them to have their spouses and extended family and friends involved especially if those people are health care providers. Encouragement to print off and share their findings with their health care providers in order that all can work together as an active health care team is also highly desireable.
The gulf war veterans are encouraged to share the information with the Medical Universities in their states. They can help by meeting with the chancellor’s office that is responsible for Medical Research. It is important to provide them with a flow of information concerning the reports published by the VA RAC GWI and other research findings that may also be pertinent, articles on Gulf war Veterans and their illnesses would trigger the additional push to have medical universities and their health care providers and their researchers to get involved.
The flow of information needs to also be targeted to their state house senators and representatives and the veterans affairs committees at their state houses. The veterans also need to keep being active and also share the information to their US Senators and Representatives through their home offices and DC offices. This is critically important to getting their staffs and elected representatives informed on a continuing basis. The veterans could seek to be involved as veterans advisory liasons to their elected representatives and senators. Encouragement could include having their elected representatives and senators to have a section of their websites dedicated to sharing critical health information on gulf war illness.
The veterans need to share the information they find with their newspapers, radio stations, and television stations. They may find valuable connections if their media resources have resident medical correspondents that can become involved. As always, the veterans should seek to involve and encourage dissemination of information to veterans service organizations in their area, fellow veterans, church groups, and even their personal facebook sites. The veterans of the gulf war are out there and some are still feeling they are alone.
You the veteran are the person that is most important. Be proactive, be sure you are getting screened for cancers, follow up immediately symptoms of heart involvement or vascular (stroke or veinous thrombus), if your body is telling you something is wrong do not delay! Get yourself in to competent medical care ER immediately. Let us save some lives in the process!
Below are the 5 research articles that are critical important. The significant area of concern or key points are highlighted and underlined and bolded for your take home message. We encourage active feedback here at VT and encourage your comments and discussion.
1. Clin Chem Lab Med. 2010 Dec;48(S1):S15-S26. Epub 2010 Nov 16.
Hypercoagulable state, pathophysiology, classification and epidemiology
Department of Internal Medicine, Medical School, University Hospital “Sestre Milosrdnice”, Zagreb, Croatia.
Abstract Hypercoagulable state is not a uniform disease. It is a complex condition with an abnormal propensity for thrombosis that may or may not lead to thrombosis, depending on complex gene-gene and gene-environment interactions. The prevalence of the hypercoagulable state depends on the ethnicity and clinical history of the population being studied. The consequences of a hypercoagulable state due to thrombosis of veins and arteries are the most important cause of sickness and death in developed countries at present. Primary hypercoagulable state is an inherited condition caused by the reduced level of natural anticoagulants due to a qualitative defect or quantitative deficiency of an antithrombotic protein, or increased concentrations or function of coagulation factors. Most of the inherited abnormalities recognized to date have little or no effect on arterial thrombosis and are associated primarily with venous thromboembolism. Arterial thrombosis usually develops as a complication of atherosclerosis and patients usually have more than one traditional risk factor. Secondary hypercoagulable states generally occur as a result of a large number of transient or permanent acquired conditions that increase the tendency for formation of blood clots. New epidemiological data and clinical trials suggest that many acquired risk factors in the pathophysiology of arterial and venous thrombosis overlap and coexist for both disorders. Clin Chem Lab Med 2010;48:S15-26.
PMID: 21077792 [PubMed – as supplied by publisher]
2. Postepy Biochem. 2010;56(3):239-47.
[Oxidative stress in haemostasis].
[Article in Polish]
Department of General Biochemistry, Institute of Biochemistry, University of Lódź, 12/16 Banacha St., 90-237 Lódź, Poland.
The normal hemostatic mechanisms consist of a balance between hemorrhage and thrombosis that is achieved through the interaction of the blood vessels, blood platelets, the coagulation and fibrinolytic factors. The vascular endothelium sustains the balance between prevention and stimulation of platelet activation, thrombogenesis and fibrinolysis and between vasoconstriction and vasodilatation. Endothelial dysfunction associated with different cardiovascular diseases is related to the local formation of reactive oxygen/nitrogen species, mainly peroxynitrite that is produced in a rapid reaction between nitric oxide and superoxide anion. Reactive oxygen/nitrogen species induce changes in the structure and function in hemostatic elements. Proteins and lipids are major initial targets in endothelial cells, blood platelets and plasma. Reaction of reactive oxygen species and nitrogen species, including peroxynitrite, with cellular proteins can lead to nitration of aromatic amino acid residues, oxidation of thiol groups and conversion of some amino acid residues into carbonyl derivative. Oxidative/nitrative modifications of platelet proteins may induce changes of their signaling and haemostatic function (activation). Peroxynitrite also causes oxidation and nitration of fibrinogen–a key protein in coagulation cascade and plasminogen (the main protein of fibrinolysisprocess) changing their hemostatic functions. Oxidative/nitrative modifications of different components of haemostasis system have been observed in several cardiovascular diseases.
PMID: 21117311 [PubMed – indexed for MEDLINE]
3. Ann N Y Acad Sci. 2010 Oct;1207:149-54. doi: 10.1111/j.1749-6632.2010.05730.x.
Combating innate inflammation: a new paradigm for acute treatment of stroke?
Stoll G, Kleinschnitz C, Nieswandt B.
Department of Neurology, University of Würzburg, Würzburg, Germany.
Interference with early steps of platelet adhesion/activation by inhibition of the von Willebrand factor (vWF) receptor glycoprotein (GP)Ib, its ligand vWF, or the collagen receptor GPVI, profoundly limits infarction in the mouse stroke model of transient middle cerebral artery occlusion (tMCAO). A similar pathogenic role was revealed for coagulation factor XII (FXII). Although these findings strongly suggest that microvascular thrombus formation is the leading pathophysiological event in acute stroke, recent studies have shown that these molecules have the additional capacity to guide inflammatory processes, thereby providing an intriguing alternative mechanistic explanation for these observations. Surprisingly, mice lacking T cells are also protected from acute stroke, and these T cell effects are antigen independent. Thus, acute ischemic stroke can be redefined as a thrombo-inflammatory disorder, and multifunctional molecules such as GPIb, GPVI, and FXII may provide new therapeutic targets linking inflammation and thrombus formation.
© 2010 New York Academy of Sciences.
PMID: 20955438 [PubMed – indexed for MEDLINE]
4. Adv Pharmacol. 2010;59:259-92.
Tissue factor in cardiovascular disease pathophysiology and pharmacological intervention.
Cardiovascular Research, Physiology Institute, University of Zurich, Zurich, Switzerland.
Tissue factor (TF) is the major trigger of the coagulation cascade and thereby crucially involved in the maintenance of vascular hemostasis. By binding factor VIIa, the resulting TF:VIIa complex activates the coagulation factors IX and X ultimately leading to fibrin and clot formation. In the vessel wall, TF expression and activity is detectable in vascular smooth muscle cells and fibroblasts and, at a much lower level, in endothelial cells and can be induced by various stimuli including cytokines. In addition, TF is found in the bloodstream in circulating cells such as monocytes, in TF containing microparticles, and as a soluble splicing isoform. Besides its well-known extracellular role as a trigger of coagulation, TF also functions as a transmembrane receptor, and TF-dependent intracellular signaling events regulate the expression of genes involved in cellular responses such as proliferation and migration. TF indeed appears to be involved in the pathogenesis of neointima formation and tumor growth, and increased levels of TF have been detected in patients with cardiovascular risk factors or coronary artery disease as well as in those with cancer. Therefore, pharmacological or genetic inhibition of TF may be an attractive target for the treatment of cardiovascular disease and cancer. Different strategies for inhibition of TF have been developed such as inhibition of TF synthesis and blockade of TF action. Clinical applications of such strategies need to be tested in appropriate trials, in particular for evaluating the advantages of targeted versus systemic delivery of the inhibitors.
Copyright © 2010 Elsevier Inc. All rights reserved.
PMID: 20933205 [PubMed – indexed for MEDLINE]
In our not-so-distant evolutionary past, stress often meant imminent danger, and the risk of blood loss, so part of our body’s stress response is to stock-pile blood-clotting factors. Scientists in the Molecular Medicine Partnership Unit (MMPU), a collaboration between the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, and the University of Heidelberg Medical Centre, have discovered how stressed cells boost the production of the key blood-clotting factor, thrombin. Their work, published in Molecular Cell, shows how cancer cells may be taking advantage of this process, and opens new possibilities for fighting back, not only against cancer but also against septicaemia, where increased blood clotting is still one of the leading causes of death.
Blood clots tend to form more often in the veins of people with cancer, a syndrome first described almost 150 years ago by French physician Armand Trousseau. In recent years, doctors have also come to realise that people with activated blood coagulation are more likely to develop cancer. Accordingly, recent studies have shown that anti-coagulants may help treat and prevent cancer, but exactly how blood-clotting and cancer progression are linked was unclear – until now.
“For the 1st time, we have something in hand that might explain this enigmatic relationship between enhanced pro-coagulatory activities and the outcome of cancer,” says Sven Danckwardt, who carried out the research within the MMPU.
The amount of thrombin our cells produce is controlled by two sets of proteins: proteins that slow thrombin production, and proteins that speed it up. Both types of protein act by binding to the cellular machinery that synthesises thrombin, and, under normal conditions, the production-slowing proteins keep thrombin levels low. But Danckwardt and colleagues discovered that, when our cells come under stress from inflammation, another protein, called p38 MAPK, reacts by adding a chemical tag to those production-slowing proteins. That tag makes it harder for the production-slowing proteins to bind to the thrombin-synthesising machinery, allowing the proteins that speed up production to take over. So inflammation caused by cancer could lead to increased thrombin levels and, as thrombin is a blood-clotting agent, this could explain why cancer patients are more likely to suffer from blood-clots. The scientists believe this new mechanism of gene regulation may apply to other genes, too.
“Knowing the exact molecules involved, and how they act, has implications for treatment, especially as drugs that inhibit p38 MAPK are already being tested in clinical studies for other conditions,” says Matthias Hentze, Associate Director of EMBL and co-director of MMPU, adding: “those drugs could be good candidates for potential cancer or septicaemia therapies.”
The Heidelberg scientists found that p38 MAPK also influences thrombin production during septicaemia. Also known as blood poisoning, septicaemia occurs when bacteria or other pathogens enter the bloodstream, leading to widespread infection and to blood-clotting problems. When they analysed liver samples taken from septicaemic mice and from cancer patients, the scientists discovered that thrombin production increases in response both to widespread inflammation during septicaemia and to localized inflammation at the tumour’s invasion front, where cancer cells are spreading into nearby tissue.
Aside from its role as a blood-clotting agent, thrombin is also involved in creating new blood vessels, and it is able to degrade the extracellular matrix that keeps cells together. So it’s possible that the cancer cells are increasing thrombin production to help the tumour spread, by making it easier to invade healthy tissue and creating blood vessels to supply the new tumour cells. This, the researchers believe, could explain why people with blood-clotting problems seem to have a higher risk of developing cancer.
“This study shows the benefits of partnerships like the MMPU, which bridge the gap between clinical and basic research,” Andreas Kulozik from the University of Heidelberg Medical Centre, co-director of MMPU, concludes.
Article: Danckwardt, S., Gantzert, A.-S., Macher-Goeppinger, S., Probst, H.C., Gentzel, M., Wilm, M., Gröne, H.-J., Schirmacher, P., Hentze, M.W., Kulozik, A.E. p38 MAPK controls prothrombin expression by regulated RNA 3’end processing. Molecular Cell, 4 February 2011.
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