Tuesday, December 3, 2013

Best article on Mast Cell and GI problems!!!

 I have tons of Gastrointestinal problems as many do who deal with Ehlers Danlos Syndrome. I am always having an episode of heartburn or gas, good thing I live alone...., and stomach cramping or severe pain and just let me tell you it gets old really fast. I don't think there is a single day that I have had in my entire adulthood without some type of stomach issue. I don't even remember what it feels like to not have pain or bubbling or cramping or something in my stomach. What that said, it is just now a way of life for me and I have learned to put up with the pain the best that I can. I have almost ever diagnoses that you can have pertaining to GI problems so I am always trying to learn more and more about what I can do to help and what it causing the problem. I do have Mast Cell Activation Disorder which plays a huge, but not complete part in my stomach issues. MCAD does all kinds of weird things to all parts of my body.  This is one of the best articles on GI problems that I have found so far. I now have come to a better understanding why with Mast Cell Activation Disorder there are so many GI problems.

Mast Cells and GI Motility Disease
© William Alford 2005


Many patients with gastrointestinal motility diseases often present with various extra-intestinal disorders that are seemingly unrelated to the problems in the gastrointestinal tract (GIT). Particularly, patients with Chronic Idiopathic Intestinal Pseudo-Obstruction (CIP) have reported incidences of Raynaud's phenomena, leukopenia, pain in the lower back or upper right quadrant, pulmonary distress, hepatitis, chronic fatigue, arthritis, headaches, recurrent septicemia, neurological deficits, parasthesias, dysesthesias, frequent candidiasis, and various autoimmune disorders. They often have disturbances of the autonomic nervous system function, which can produce orthostatic hypotension; heart palpitations; disturbances of vision, perspiration, and motility; and venous pooling. Various allergies have been reported with itching, hives, edema, rashes, and flushing. These last symptoms are also normally the result of histamine release from mast cells.
Mast cells have long been known to contribute to the discomforts of mankind by releasing histamine and producing the miseries of allergies. However, patients with mast cell disease may also present with a multitude of disparate symptoms such as arthritis, GERD, constipation, malabsorption, cramping, severe abdominal bloating, mitral valve prolapse, short term memory problems, headache, nausea, dizziness, interstitial cystitis, vasculitis, spontaneous bruising, diarrhea, flushing, heart palpitations, sudden blood pressure rises or drops, osteoporosis, bone pain, changes in cognitive function and mood, and even severe anaphylactoid reactions with shock (Wolff). Is it possible that with such a significant overlap of symptomotology, that a diagnosis of illness might depend on the route of medical investigation?
The mast cell was first named by Paul Erlich in 1887 because of its appearance. All the clustered metachromatic granules in the cell reminded him of a “well fed cell”, and thus the name Mastzellen from the German. While mast cells are generally ubiquitous and present throughout the body, all body tissues that come in direct contact with the outside world have mast cells and they are most concentrated in the skin, gut, nasal passages, lung, urinary tract, and other mucus membranes. Each “well fed” mast cell can contain up to 500 granules that store a variety of molecules including arachidonic acid products, biogenic amines, cytokines, neuropeptides, chemoattractants, proteoglycans, and proteolytic enzymes (Theoharides). However the principle chemical mediator of mast cells is histamine which can cause tissue swelling, itching, flushing and other noxious skin responses. It is what causes the itching and swelling of the mosquito bite and the itch of healing wounds with the rapid growth of new tissue. But it can also cause systemic responses such as headache, nausea, dizziness, and diarrhea, and can be involved in other GI disease such as gastric ulcer and IBS.
In fact histamine is the most important paracrine secretion in the stomach and it is thought that paracrine secretions may also function as neurotransmitters in the gut. Histamine, gastrin and acetylcholine are the most important local controls of acid secretion in the stomach where it binds to specific H2 receptors, and H2 receptors in the stomach are10 times more sensitive to histamine than those in blood vessels. Histamine has a steady basal release in the gut but is increased when Gastrin or Acetylcholine secretion is increased (Rang). It is also a “neuroactive” mediator and can affect the blood pressure directly. Of the four types of histamine receptors that have been recognized pharmacologically, three are located in the gut and a series of experiments with dispersed colon mast cells has shown that at least two pathways could exist for mast cells to amplify their own activation-degranulation signals in an autocrine or paracrine manner (Xie).
Although mast cells derive from stem cells in the bone marrow, they are not found in the peripheral blood, but their precursors may be found in the bone marrow, blood, mucosal and connective tissues. When the precursors are appropriately stimulated they proliferate and differentiate into mast cells and then can reside in the tissues for months or years. The wide distribution throughout the tissues and their ability to increase their numbers dramatically during various pathological conditions have led to many conjectures about their function. It has been postulated that they may have a role in regulation of gastric acid, the microvasculature, and even the repair of connective tissue, but their role in allergic inflammation and atopic illness have remained the focus of attention (Stenton).
Historically mast cells have been thought of as the “cry wolf” cells of the body, the “alarm bells” that overreacted to allergens and seemed to have no other function. However, more recent understandings of the function of mast cells indicate that many of these responses are only the side effects of their real role as potent regulators of the immune system. Researchers at Duke University Medical Center reported in the July 6, 1999 issue of the Proceedings of the National Academy of Science that they had discovered that mast cells recognize harmful bacteria and trigger the body's innate immune system by releasing tumor necrosis factor (TNF) and recruiting neutrophils, the infection-clearing cells. Mast cells can selectively produce different classes of mediators in response to specific pathogens, thereby allowing the selective recruitment of specific cell types, such as neutrophils, eosinophils, dendritic cells, and T cells (Marshall).
The human immune system has two parts, the innate, which yields the first line of defense against illness, always with the identical immediate response triggered by any invading pathogen, and the adaptive, which tailors a response to a specific pathogen. The innate system attacks the pathogen for the first few days until the adaptive response is primed. When the adaptive immune system is triggered, lymph nodes recruit T-cells, which proliferate and sensitize B-cells to produce very specific antibodies targeting the particular pathogen. The swelling of the lymph nodes is an indication that the adaptive immune system is active.
When Duke University scientists introduced bacteria into mutant mast cell-deficient mice, their lymph nodes did not swell, but these same animals' nodes did swell when they were injected with mast cells. Also, activation of skin mast cells produced a rapid rise in TNF in the lymph nodes along with the recruitment of T cells indicating that mast cells are a part of both the innate and adaptive immune systems.
The Duke team's discovery also explained the function of the CD48 protein. Discovered over ten years ago on the surface of mast cells, the Duke team showed that antibodies to CD48 will block mast cells from recognizing bacteria and releasing the signaling molecule TNF-a. This indicates that the CD48 receptors on mast cells are specific to recognizing bacteria and alerting the immune system to attack them.
Dr. Salvatore Pizzo, a member of the Duke University Research team, has said, "When you pick up a textbook two years from now that shows how the immune system functions and the way a node responds to an infectious agent, you are going to see a whole new pathway," and that it may very well be, “ . . . a major shift in the understanding of the immune system.”
So, with this current understanding of the role of mast cells in the immune system, what constitutes pathology?
Mastocytosis (MC) is a disease characterized by abnormal growth and accumulation of mast cells. This can occur in the skin, in internal organs, or in both. The disorder produces too many mast cells and so activation can release a much greater concentration of chemical mediators with the resultant systemic reactions. In cutaneous mastocytosis (CM) accumulation is only in the skin, whereas in systemic mastocytosis (SM), accumulation is found in internal organs. In contrast to a reactive mast cell increase during an inflammation, mast cells in systemic mastocytosis (SM) are monoclonal in nature, i.e. derived from a single abnormal cell clone. While the cutaneous form of mastocytosis (CU) usually appears in early childhood, most patients that are diagnosed as adults have systemic mastocytosis (SM), and most, but not all, will have the skin lesions known as Urticaria Pigmentosa (UP). For a diagnosis of CM, a biopsy of the skin may be sufficient and in one study skin biopsies taken from UP lesions contained roughly 600 mast cells per square millimeter, compared to about 40 mast cells in the same area in normal skin. However, some patients have a lower mast cell load and there is really no reliable cut-off point that can indicate if a mast cell count is within the limits of normal skin, or whether it is increased (Wolff).
A diagnosis of SM in adults can best be established by bone marrow biopsy. However, many false negatives have been reported from first biopsies and the presence of excess mast cell progenitors may be only a sufficient but not necessary condition. In other words, a positive bone marrow biopsy will definitely indicate SM, but a negative biopsy does not rule it out. While not as reliable, another test is the alpha pro-tryptase test, performed by Dr Lawrence Schwartz in Virginia, or the 24-hour N-methyl histamine test (not the regular urine histamine test). It would seem reasonable that if chronic GI dysmotility was accompanied by extra-intestinal symptoms that at least a tryptase test would be valuable in evaluating the root of the illness. Dr. Theoharides at Tufts University School of Medicine has indicated an interest in working with researchers in our field by doing tryptase and IL6 testing in   his laboratory. From his experience, the IL6 level is a better index of disease involvement. All that would be required would be spinning down the serum from a blood draw in a red-top vial and sending it frozen to his address after the patient has spent several days without taking any antihistamines. This would seem to be an excellent project for a grant proposal.
Many patients with urticaria and mast cell disease have tested positive with the autologous serum skin test (ASST). In this test, the patient's own blood is spun down and separated into plasma that is then injected back under the skin. A wheal at the injection site usually indicates an autoimmune disease. And in the book, "Urticaria and Angioedema," by Drs. Greaves and Kaplan, the basophil histamine release test is described to confirm a positive ASST.
There is also the mast cell activation disorder. In this case either a greater or even a normal number of mast cells may be “twitchy” or too easily activated by stimuli and may even be activated by autoantibodies. For these patients, symptoms may appear from the release of mediators when a histamine threshold has been reached. If one thinks of a “histamine bucket” representing some critical level at which symptoms appear, then any addition to this “bucket” is a burden that commands attention. When some cumulative load from stress, environmental activating stimuli, endogenous histamine, and ingested histamine cause the bucket to “overflow”, then the appearance of symptoms can manifest. Patients whose symptoms wax and wane over time may fall into this category as their histamine “load” varies with circumstance.
Histamine is released by mast cells when some trigger stimulates them, but it can also be found in all food as part of the natural spoiling process and can reach a reactive level in human beings long before any signs of spoilage occurs. Bacteria convert the amino acid histidine, found in all proteins, to histamine. Some foods, such as cheese and other fermented foods like alcoholic beverages and vinegars have high histamine levels due to fermentation during the manufacturing process. Fin fish can develop high levels of histamine in the flesh from bacteria in the gut of the fish with levels rising with the time from catch to dressing of the fish. And then some foods have high levels of histamine that occur naturally, such as eggplant and spinach. And it appears that the inhibition of intestinal histamine-metabolizing enzymes by various mediators can cause a decrease in histamine detoxification in the intestinal mucosa resulting in increased intestinal uptake and urinary excretion of unmetabolized histamine (Taylor). Also, quite a few food additives such as dyes and preservatives can trigger the release of histamine. The excellent book entitled Dietary Management of Food Allergies and Intolerances by Janice Vickerstaff Joneja, Ph.D, RDN, lists two histamine restricting diets that may be of value to those with this symptomatology since limiting any additional source of histamine to the trigger threshold could help to control the disease. A list of foods that contain histamine has been supplied to AGMD as a resource for patients that might have MC.
That food allergy can produce symptoms at other physical sites has been a puzzle to the medical community. A food allergen often produces GI symptoms such as diarrhea, abdominal pain, vomiting, or bloating, but some patients also rapidly develop such symptoms as asthma, rhinitis, urticaria, arthritis, or migraine. It has been postulated that histamine from gut mast cells might bind to sensory nerves and produce an afferent signal that the CNS could route to another site—a response known as neurogenic switching. Sick building syndrome and multiple chemical sensitivity are other maladies that might be explained by neurogenic switching shunting inflammatory stimuli to a remote flare at the diseased site. The time of onset from neurogenic switching depends only on nerve conduction velocity while immunogenic switching would depend on circulating times in the bloodstream and diffusion time in the tissues, thus explaining the rapid onset of symptoms. And it has been shown that vagotomy will protect rats from lethal anaphylaxis without changing the production of either antibody or histamine release, indicating a neuronal pathway as a mechanism of action; but the role of the mast cell is again paramount (Meggs).
Since mast cells have such a profound involvement in the normal immune system response, an involvement in autoimmune disorders might be expected, and in fact, in the March 2000 issue of the Journal of Experimental Medicine, scientists at the Emory University School of Medicine reported the discovery of a connection between mast cells and the development of Multiple Sclerosis (MS). MS is a well-known autoimmune disease that damages the central nervous system by attacking the protective myelin sheath that lines the nerve cells, leading to impairment of nerve function. Previously, most research into MS has focused on the idea that T cells attack the myelin sheath, but the Emory researchers took note of the recent appreciation that mast cells are prevalent in the central nervous system and produce many of the same cytokines and proteases/enzymes that are known to contribute to myelin sheath degradation. Then by using mutant mast cell-deficient mice, they attempted to induce the mouse equivalent of MS, a mouse disease called experimental allergic encephalomylitis (EAE), by injected myelin proteins known to cause EAE. The mast cell-deficient mice had a greatly reduced EAE incidence, but again, when mast cells were injected into the mice, the disease severity was restored to levels seen in normal mice. Dr Melissa Brown, an Emory University pathologist on the team speculates that since mast cells are in close proximity to blood vessels in the CNS, the release of histamine, known to cause vasodilation and leakage of blood vessels, could open the blood brain barrier and allow the access to other damaging cells such as the T cells, as well as releasing other directly damaging proteases directly from the mast cells themselves (http://wwwsciencedaily.com/releases/2000/03/000308081524.htm), and it has been shown that breakdown of the blood-brain barrier has preceded any clinical or radiographic signs of MS (Theoharides). This new appreciation of the likely role of mast cells in MS also raises the question as to whether drugs such as cromolyn sodium antihistamines used to treat mast cell disease would be effective in treating MS.
The gut biopsy specimens of patients with inflammatory bowel diseases have been examined for histamine release. When specimens were compared to control subjects, the mast cell count in patients with ulcerative colitis was increased and the mast cell count from inflamed tissue was greater than that of normal tissue, and at anti-IgG4 challenge, histamine release was generally confined to patients with inflammatory bowel disease suggesting that mast cells may play a part in inflammatory bowel disease (Nolte).
Researchers at the University of Sydney Department of Medicine have reported that intestinal mast cell degranulation from a prior enteric infection or allergy may play a part in gut hypersensitivity in Irritable Bowel Syndrome both in motor response and visceral perception and that psychological stress may trigger this via the brain-gut axis (Gui). Furthermore, investigators at a medical institute in Amsterdam have proposed that microscopic inflammation of neurogenic origin (invisible at endoscopic investigation) is responsible for the altered motility and sensitivity to pain in the GIT as the result of mast cell activation with the chemoattraction of inflammatory cells from the bloodstream as the most important step in the pathogenic cascade that can alter motility and sensitivity along the entire GIT. When the Amsterdam group set up experimental animal models for stress-induced IBS and post-operative ileus, they observed that motility changes were indeed preceded by the occurrence of local inflammatory sites and that prevention of this inflammation normalized motility (Boeckxstaens).
So, we have seen that similar symptoms may present with idiopathic GI motility disease and with mast cell disease. We should also appreciate that many of the drugs used for nausea, vomiting, and abdominal cramping, such as elavil are also potent antihistamines. Doxepin is often prescribed for depression associated with chronic illness and it is also a potent blocker of H1 and H2 receptors. Periactin is often prescribed to promote weight gain and is used as a sedative for psychiatric patients and is also an H1 antagonist. Research on rodent mast cells have shown that benzodiazepines, including valium, can bind directly to mast cells and thereby inhibit the mast cells from releasing excessive mediators. Often patients may be prescribed drugs for stress when exotic illnesses confound the treating physicians, so it could be that in some cases the right drug is being given for perhaps the wrong reasons.
When Dr. Thomas Abell was at UTBowld Hospital in Memphis, his research team examined many full-thickness intestinal biopsies of patients with motility diseases and he has reported edema in the intestinal wall, an infiltration of lymphocytes, and often a high level of circulating non-specific auto-antibodies (Abell). While the lymphocytic infiltration may be indicative of some as yet unknown pathogen (Smalley), could it also be the result of the chemoattractant recruitment by mast cell mediators? Could the edema found in the intestinal wall be the result of histamine release and the subsequent tissue swelling that it is known to produce from blood vessel leakage? Are the circulating autoantibodies somehow related to autoimmune urticaria, which can be triggered by autoantibodies? I have attached in the appendix color photographs taken from the website of The Wasa Workgroup on Intestinal Disorders in Vasa, Finland (http://www.gastrolab.net/ku27.htm). These photographs show patchy white lesions on the wall of the throat and esophagus that the researchers think may be urticaria in the GIT (Bjorknas). And one wonders what results would be obtained if future intestinal biopsies were examined for evidence for the proliferation of mast cells.
Patients with urticaria and mast cell disease are typically treated with various combinations of antihistamines which block histamine receptor sites on cells, with a fine-tuning of both dosage levels and drug choice often being very specific to the patient. A very successful choice is the well-known “ZZ” combo of zyrtec and zantac since this combination blocks both the H1 and H1 receptors. Other antihistamines include ChlorTrimeton, Benadryl, Dramamine, Claritin, and Tavist. The anti-leukotrienes such as Singulaire have also been of value in the successful drug cocktails. Compounds that both block the release of histamine from mast cells and antagonize H1 receptors include azelastine, ketotifen, permirolast and others. It should be noted that since many other mediators are released from mast cells in addition to histamine, those strategies that prevent mast cell degranulation are of greater value.
In this light, there is a published account of the remediation of ileus due to mast cell involvement that warrants attention. US patent number 5,958,407 was issued in 1999 to the University of California at San Francisco and the details released through their Office of Technology Management. The patent was issued for the “Methods for the Treatment of Post-operative Ileus”. More specifically, the description is for treating post-operative ileus by preventing mast cell degranulation via administration of specific compounds. From the title this would seem very specific to surgical situations, however, investigating the patent description in depth suggests that the mechanism of action that induces ileus in healthy individuals following surgical manipulation might also apply to persons with idiopathic GI motility issues that might involve mast cell degranulation.
The loss of intestinal motility, termed post-operative ileus, is a major complication of abdominal surgery often resulting in long hospital stays. The trauma of abdominal surgery and the consequential intestinal manipulation causes infiltration of mast cells and their degranulation, resulting in the release of the enzymes tryptase and chymase. Both of these enzymes can cleave proteinase-activated receptor 2 (PAR-2) on colonic cells releasing the N-terminal SLIGRL peptide agonist of PAR-2 resulting in bowel stasis. There are pro-inflammatory mast cells present in the intestinal wall and the manipulation of the intestines results in inflammation and further influx and degranulation of mast cells. It is the infiltration and degranulation of mast cells in the colon that release tryptase and chymase, which activates the PAR-2 receptor.
Earlier this author has postulated that circulating endotoxins from a leaky gut could contribute to the extra-intestinal symptoms of CIP (Alford). The increased intestinal permeability leads to the leaking of endotoxin into the peripheral circulation, which can cause various disease processes throughout the body. Injection of laboratory mice with endotoxin has been shown to produce auto-antibodies and soluble immune complexes in the blood, with individual mice showing marked differences in circulating immune complex responses (Bloembergen). Since up to 50% of patients with chronic urticaria (CU) have circulating auto-antibodies that are thought to provoke the CU, it may be that a positive feedback loop is maintained with the activating of mast cells by the circulating auto-antibodies perpetuating the release of endotoxin, which produces more circulating auto-antibodies with mast cell activation.
Prior to this patent claim by the University of San Francisco group, extreme cases of post-operative ileus were treated with surgical intervention or with drugs to increase the colon's motility. The patent claims that these approaches have historically been ineffective in dealing with the problem of ileus and its complications and that their described method based on the discovery that proteinase-activated receptor 2 is expressed in colonic muscle and that activation of PAR-2 inhibits GI motility has great efficacy for preventing or resolving the ileus. It is claimed that their method of treatment accelerates recovery by preventing mast cell degranulation, inhibiting tryptase and chymase, and antagonizing PAR-2 (US Gov. Patent Office Website).
The author has included an abridged form of the patent description in an appendix and the entire patent description can be read in detail on the US Government Patent Website at – http://patft.uspto.gov/netahtml/srchnum.htm—which also describes the evaluation of appropriate compounds as well as their treatment method.
The new appreciation of the role of mast cells in the immune system and the consideration of a role for mast cell involvement in the GI motility diseases is engaging and could provide an interesting direction of investigation and treatment, particularly in the subset of patients that also exhibit allergies and have evidence of flushing, hives, unusual solitary bumps anywhere on the body, or have autonomic dysfunction or GI symptoms that wax and wane. A closer look at the treatment for mast cell disorders may yield new strategies for GI motility dysfunction.
A short list of principal investigators in the MC arena is provided in appendix ii for further information and dialog.



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ADDITIONAL REFERENCES
References Below From: Unmasking Mastocytosis, Richard L. Pullen, Jr., EdD, RN, Kim Carrington Wright, MSN(c), RN
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Roberts, L. J., Anthony, L.B., & Oates, J.A. (1998). Disorders of vasodilator hormones: Carcinoid syndrome and mastocytosis. In J.D. Wilson, D.W. Foster, H.M. Kronenberg, & P.R. Larsen (Eds.), Williams Textbook of Endocrinology (9th ed.) (pp. 1711-1732). Philadelphia: W.B. Saunders Company.
Soter, N.A. (2000). Mastocytosis and the skin. In D.D. Metcalfe & N.A. Soter (Eds.), Hematology/Oncology clinics of North America: Mast cell disorders (p. 537-555). Philadelphia: W.B. Saunders Company.
Tharp, M.D., & Longley, B.J. (2001). Mastocytosis. Dermatologic Clinics, 19, 679-696.
Tharp, M.D. (1995). Mast cell disease and its diagnosis. Journal of Investigative Dermatology, 104, 885-886.
Valent, P., Horny, H., Escribano, L., Longley, B.J., Li, C.Y., Schwartz, L.B., Marone, G., Nunez, R., Akin, C., Sotlar, K., Sperr, W.R., Wolff, K., Brunning, R.D., Parwaresch, R.M., Austen, K.F., Lennert, K., Metcalfe, D.D., Vardiman, J.W., & Bennett, J.M. (2001). Diagnostic criteria and classification of mastocytosis: A consensus proposal. Leukemia Research, 25, 603-625.
Wolff, K., Komar, M., & Petzelbauer, P. (2001). Clinical and histopathological aspects of cutaneous mastocytosis. Leukemia Research, 25 (7), 519-528.
Worobec, A.S. (2000). Treatment of systemic mast cell disorders. In D.D. Metcalfe & N.A. Soter (Eds.), Hematology/Oncology clinics of North America: Mast cell disorders (pp. 659-687). Philadelphia: W.B. Saunders.
APPENDIX i Selection from the US Government Patent # 5,958,407 http://patft.uspto.gov/netahtml/srchnum.htm
BACKGROUND OF THE INVENTION
Inhibition of intestinal motility, especially colonic motility, is a major complication of abdominal surgery. The condition, termed post-operative ileus, delays the normal resumption of food intake after surgery and often leads to prolonged hospitalization.
Mast cells are pro-inflammatory cells that are normally present in the wall of the intestine. Manipulation of intestine and intestinal inflammation are accompanied by influx and degranulation of mast cells in the wall of the intestine (Vermillion). Mast cell tryptase and chymase are proteases that account for 25% of the total protein of mast cells (Caughey). They are released from mast cells upon degranulation within the wall of the colon.
Heretofore, postoperative ileus has been treated, in extreme cases, with surgical intervention to unblock the colon. Ileus may also be treated with drugs that act to increase colonic motility, such as Leul3-motilin and prostaglandin F2 alpha. However, these approaches have generally been ineffective in significantly reducing the period of postoperative ileus and its complications. It would therefore be useful to provide a more effective method of treating post-operative ileus, in particular, to accelerate recovery time following colonic surgery.
SUMMARY OF THE INVENTION
The present invention is directed to a method of treating or preventing post-operative ileus in a mammalian subject. The method includes administering to the subject, a pharmaceutically effective amount of a compound that is effective in (i) preventing mast cell degranulation, (ii) inhibiting tryptase and chymase, or (iii) antagonizing PAR-2.
The treatment is based on the discoveries that proteinase-activated receptor 2 (PAR-2) is expressed in colonic muscle cells, and that activation of PAR-2 inhibits colonic motility. The PAR-2 receptor is activated, at least in part, by tryptase and chymase, produced by infiltration and degranulation of mast   cells.
For preventing mast cell degranulation, the compound is preferably cromolyn, doxoantrazole, quercetin, tranilast, ketotifen, tiacrilast, azelastine, lodoxamide, mepyramine, picumast, or water-soluble constituents of the Ginkgo biloba episperm.
For inhibiting tryptase, the compound is preferably leech-derived tryptase inhibitor, APC-366, and BABIM and related amidines, TLCK, GMCHA-Ophbut, or a dipeptide tryptase inhibitor.
For inhibiting chymase, the compound is preferably chymostatin, chymostatin analogues, .alpha.-1-antichymotrypsin.
For antagonizing PAR-2, the compound is one capable of inhibiting the mobilization of Ca.sup.+2 in cells transfected with the PAR-2 gene, and stimulated by trypsin or activating peptide (SLIGKVD-NH.sub.2 and SLIGRL-NH.sub.2, for human and murine PAR-2, respectively).
Where the treatment compound is a polypeptide, such as leech-derived tryptase inhibitor, chymostatin, chymostatin analogues, and .alpha.-1-antichymotrypsin, the compound may be delivered by orally administering a DNA construct capable of transfecting colonic cells, and expressing the polypeptide in the colonic cells.
For orally active compounds, such as cromolyn, doxoantrazole, quercetin, tranilast, ketotifen, tiacrilast, azelastine, lodoxamide, mepyramine, picumast, water-soluble constituents of the Ginkgo biloba episperm, APC-366, BABIM and related amidines, TLCK, and GMCHA-Ophbut, the compound is preferably administered orally. Alternatively, the compound may be administered by parenteral route, such as intraperitoneally or intravenously.
In another aspect, the invention includes a method of identifying compound candidates for use in treating post-operative ileus. The method includes screening test compounds for their ability to inhibit the mobilization of Ca.sup.+2 in cells transfected with the PAR-2 gene, when the cells are stimulated by trypsin or activating peptide ((SLIGKVD-NH.sub.2 or SLIGRL-NH.sub.2), and selecting the compound as a candidate for the treatment if significant inhibition of Ca.sup.+2 mobilization in the cells, when compared with activated cells in the absence of the compound, is observed. ILEUS MAST CELL PATENT REFERENCES Armstrong, R. W., PCT Intl. Appn. Pubn. No. WO 9502566 (January 1995).
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Caughey, G. H., Ed., MAST CELL PROTEASES IN IMMUNOLOGY AND BIOLOGY, Marcel Dekker, Inc., New York, N.Y. (1995).
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Harvima, I. T., et al., Arch. Dermatol. Res. 285(4):184-192 (1993).
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Nystedt, S., et al., J. Biol. Chem. 270(11):5950-5955 (1995).
Pohlig, G., et al., Eur. J. Biochem. 241(2):619-626 (1996).
Richards, D. M., et al., Drugs 27(3):210-231 (1984).
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Takei, M., et al., Biol. Chem. Hoppe Seyler 370(1):1-10 (1989).
Tomkinson, N. P., Biochem J., 286(2):475 (1992).
Vermillion, D. L., and Collins, S. M., J. Gastrointest. Mot. 5:1-8 (1993).
Walter, M., et al., Arch. Biochem. Biophys. 327(1):81-88 (1996).
APPENDIX ii BIO OF SELECT MASTOCYTOSIS RESEARCHERS IN USA
Dr. Cem Akin, MD., Ph.D.
Dr. Cem Akin is an Assistant Professor at University of Michigan's Department of Medicine - Division of Allergy and Clinical Immunology, where he heads a new research facility, one of the few in the country devoted to the research of Mast Cell Disease. Here he leads a team which conducts studies of cellular and molecular pathologic mechanisms in mast cell disorders. Formerly of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Dr. Akin established himself there as a leading mast cell researcher (receiving the Staff Recognition Award for 4 consecutive years of 2000-2003) and developed novel techniques for identifying mast cell disease and determining the most promising treatment options for patients. Dr. Akin is the recipient of the TMS (The Mastocytosis Society) research grant of $44,000. Dr. Akin's new research facility at University of Michigan will continue his critical studies as he establishes a Center for both Mastocytosis patient care and for research in collaboration with faculty from the University of Michigan Comprehensive Cancer Center and the Division of Allergy and Clinical Immunology. In his clinic, Dr. Akin diagnoses and treats mast cell diseases in people referred by doctors throughout the country, including patients with unexplained symptoms who need specialized testing. Dr. Akin serves on the American Academy of Allergy, Asthma, & Immunology Mast Cell DisordersTask force and the TMS Medical Advisory Board. He is also a consultant for The Mastocytosis Society, Canada Mastocytosis Support, and the European Competence Network on Mastocytosis.
Dr. Mariana Castells MD, Ph.D.
Dr. Castells is a clinician/teacher at the Brigham and Women's Allergy Services, the Co-Director of the Allergy and Clinical Immunology Training Program at the Brigham and Women's Hospital, a researcher in the mast cell biology group, and an Assistant Professor of Medicine at Harvard Medical School. As a researcher Dr. Castells has her own independent research laboratory which studies mast cell inhibitory receptors and desensitizations. Taking particular interest in drug adverse reactions, anaphylaxis, Mastocytosis, physical allergies including exercise induced anaphylaxis, food allergies, urticaria, and immunodeficiencies, Dr. Castells receives nationwide and international patient referrals. Dr. Castells specific interest in Mastocytosis has prompted the establishment of the Mastocytosis Registry (a registry for patients), of which she is Director. Dr. Castells also donates her time as Advisor to TMS.
Dr. Joseph H. Butterfield, MD.
Dr. Butterfield is a Consultant at the Mayo Clinic's Department of Immunology in Rochester, Minnesota and a Professor of Medicine at the Mayo Clinic College of Medicine. In 1985 Dr. Butterfield successfully cloned an immature mast cell line from the peripheral blood of a patient with Mast Cell Leukemia, and thus holds the prestige of being the inventor of the Human Mast Cell Line HMC-1. Since then he has seen more and more Systemic Mastocytosis patients along with patients of disorders of the release of mast cell mediators. Due to the great volume of these patients seen by Dr. Butterfield, Systemic Mastocytosis now plays a primary role in his clinical practice, and new patients appear on a weekly basis both nationally and internationally. Dr. Butterfield is an accomplished speaker, presenting his research worldwide on international and national levels. Dr. Butterfield serves as Advisor to TMS. Over the past 20 years he has devoted himself to improving the treatment of patients with Systemic Mastocytosis.
Theoharis C. Theoharides, Ph.D., M.D.
Professor
Tufts University School of Medicine
136 Harrison Avenue
Boston, MA 02111
Phone: 617-636-6866
Fax: 617-636-2456
Email: Theoharis.Theoharides@Tufts.edu 
Dr. Theoharides has ongoing research interests in four related areas: (a) molecular events involved in mast cell stimulus-response coupling in allergic reactions and in the pathophysiology of inflammatory disorders: atopic dermatitis, arthritis, coronary artery disease, as well as in interstitial cystitis/chronic prostatitis, migraine headaches and multiple sclerosis for which Dr. Theoharides' group has developed in vivo and in vitro models; (b) the ability of mast cells to release some of their mediators, especially cytokines, selectively that may explain how they participate in inflammation; moreover, selective release of angiogenesis factors may help explain the high number of mast cells around tumors, such as breast carcinoma and melanoma; (c) the role of mast cells in mediating the effect of stress by responding to corticotropin-releasing hormone (CRH), or its analogue urocortin (Ucn), with cytokine release, as well as secretion of CRH and Ucn; (d) the regulation of the expression, identification of the phosphorylated sites, as well as molecules that increase and sustain the phosphorylated state of a 78 kDa mast cell phosphoprotein he and his associates have cloned. In its phosphorylated state, this protein inhibits mast cell secretion and proliferation; select compounds could serve as anti-allergic/anti-inflammatory drugs, and possibly anticancer agents. Dr. Theoharides has numerous patents and is interested in using natural molecules in food supplements for the treatment of allergic/inflammatory and malignant conditions (Related web site: Algonot.com). He is also interested in drug and biomedical research policy. He has served as the Clinical Pharmacologist of the Massachusetts Drug Formulary Commission continuously since 1986; he has also served on the Supreme Health Council, of the Ministry of Health, the HealthCare Board of the Ministry of Labor and Human Resources and the National Drug Organization of the Hellenic Republic.
Dr. A. P. Kaplan
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Allergy and Clinical Immunology, Medical University of South Carolina, Charleston, SC 92425, USA. kaplana@musc.ed



Monday, June 17, 2013

Has Your Chronic Illness Destroyed Your Dreams Or At Least Changed Them?

What is your dream or dreams in life? Most of us with Ehlers-Danlos or other chronic illness might say to live pain free, or take less meds. I know for me that would be great! I also know that EDS and the other illnesses that I have have gotten in the way of my dreams. Today though, I want to go dream walking for a bit. So I am sharing two videos with you. One of a dream that is being resurrected so to speak, and one dream that already came true.

I have many dreams of what I want to do, and one of them is voice acting. You know doing commercials and narrative things. I actually made a demo tape, notice I said tape, a long time ago, and shopped it around a bit, but nothing ever came of it and then of course tapes went to the wayside. Good thing I am resourceful though! I had recorded the tape onto my computer putting a microphone up to the tape player's speaker and then put it in a Power Point file. I had to find out how to take the sound file from there and save it on my computer to use for other things. So, I made a video with my now new in any format that I want, Voice Acting Demo. Who knows?..... I might even get a real job doing that one day!



The biggest dream of my life, I have had it since the age of 3, and that dream was to be a missionary. At the age of 9 I dedicated my life, before God and the world, as I said that I would be a missionary when I grew up. During those growing up years I did missions all the time in Mexico with my church and later with a missionary family that lived there.

In 2001 I moved to NYC, and I got there the day before 9/11 which is another story for another time, to prepare to go to Nigeria. Well, as a result of 9/11 I was unable to travel to Nigeria at that time so I returned home. Four years later I finally made it to Nigeria.

There is one thing that I want to say about Nigeria besides that it is beautiful and a great experience, and that is ....that IT IS HOT THERE!!! My health was not good by any means at that time, but I just thought that was just the way life was for everyone, I mean feeling bad and being sick all the time. I didn't know then that I had Ehlers Danlos Syndrome. I look back now and know for sure that it was only by God's Grace that I survived Nigeria's heat. The Nigerians come to Texas and say that it is hotter here than there. I can come up with several points to counteract them with.....lol....

I am telling you about Nigeria because my heart longs to go back and serve those people. My heart is very connected to the Nigerians and my heart is also broken that I cannot return to Nigeria nor can I do much here at home for the Nigerian people. If you have Ehlers-Danlos, or P.O.T.S., or any other chronic illness then you know what it is to have a broken heart because more than likely you too have had to give up on a dream or two.

Well, I count myself so incredibly blessed to have been able to live in Nigeria and be a foreign missionary that sometimes I can't contain that blessing inside and I just have to let it out. So I am kinda doing that here by sharing a video that I made of my mission in Nigeria. I love that country and I love the people there and I truly miss my friends there greatly!

I hope that you will find some joy, or passion, or just maybe some amazement from my video. I also am reminding myself that just because I can't go back to the foreign mission field, that I am still a missionary and I still have a mission to do and now that mission is reaching those that I see in the medical community.

To my Nigerian friends, if you see yourself in the video don't get upset with me, instead just count yourself as either a servant of God to bring others to Him, or count yourself as a new Star that is breaking through the old hoo hum of everyday life. ;) Oh and don't worry, your name is not anywhere in the video

Ok.... here is the video!

I would love to hear from you about how your dreams have been altered or destroyed by your chronic illness or circumstances in life. Please feel free to leave a comment.

Saturday, June 8, 2013

So You Think You Might Have EDS?





Do you ever feel like screaming this out to everyone who doubts you when you have things hurting on or in your body and no one believes you and even yourself, you don't know why this or that is happening? Well, read this article from Ehlers-Danlos National Foundtaion website and see if you fit in this group or not.

So You Think You Might Have EDS?


By Sue Jenkins RN
with contributions from Liza Sauls
http://www.ednf.org/images/stories/leaflets/soyouthinkyoumighthaveeds.pdf


It has been the experience of many of our members that a final diagnosis of EDS is the result of 'connecting the dots' of a person's history and a comprehensive review of the constellation of all symptoms; and includes, for many, thorough review of the
medical histories of their families as well. Finally getting the diagnosis can be a relief to know that the symptoms are real and have a name; however limitations occur here as well. There is no cure, no 'fix', simply because the collection of experiences and symptoms now has a name and identity. But it does allow the patient and their
families to know what they may be facing and allow them to become educated and proactive about the care they seek and require.

Based on the accumulated experiences of our members, the following essay is an overview of many of the symptoms and conditions that can be associated with EDS. It is not meant as a substitute for thorough medical review and care and supervision, but to help to view some aspects of EDS. Not every patient will have every symptom,
as you will see, EDS can manifest in many different ways. The challenge of EDS is not to be able to identify each symptom, but to be able to see a pattern among several. Early diagnosis and intervention are the keys to living the best life possible.
With the recent TV programs on Ehlers-Danlos Syndrome, many people are coming to this website with questions about having EDS. Here is a list to help you determine if you need to see a geneticist who can correctly diagnose you.

Caution:
If after reading the following article, you think you may have EDS, be
sure to seek medical advice. Please do not rely solely on this article or end your search with a self diagnosis.

EDS is a genetic syndrome and is diagnosed by a specialist, 
usually a geneticist or rheumatologist with extensive 
knowledge about EDS and its types: 

• Classical, 
• Hypermobile, 
• Vascular, 
• Kyphoscoliosis, 
• Arthrochalasia, 
• Dermatosparaxis 

Ehlers-Danlos Syndrome is a group of disorders that affect connective tissues, which are tissues that support the skin, bones, blood vessels, eyes and other organs. Defects in connective tissues cause the signs and symptoms of Ehlers-Danlos Syndrome, which vary from mildly loose joints to life-threatening complications related to tissue structure and fragility.

A physical examination is required, including taking an extensive family history and using the Beighton scale, which measures Hypermobility. Depending on which type of EDS the physician believes you have, either a blood test or muscle biopsy will be taken.

How You Get It:
EDS is a genetic disorder, a mutation of one or several genes that make different types of collagen in your body, producing a defective tissue. A mutation in a gene on one of the first 22 nonsex chromosomes can lead to an autosomal disorder. Genes come in pairs.
Some types of EDS are autosomal dominant and others are autosomal
recessive. Differing types of EDS affect different types of collagen.
• If a disease is autosomal dominant, it means you only need to get
the abnormal gene from one parent in order for you to inherit the
disease. One of the parents may often have the disease. Each child
has a 50/50 chance of inheriting this disease.
• Recessive inheritance means both genes in a pair must be defective
to cause disease. People with only one defective gene in the pair
are considered carriers. However, they can pass the abnormal gene
to their children.

Wrong Diagnoses:
Most people diagnosed with EDS have come the same long road where
it seemed that nobody knew what was really wrong with you. Diagnoses of
• osteoarthritis,
• fibromyalgia,
• lupus,
• rheumatoid arthritis,
• rheumatic fever,
• multiple sclerosis,
• “growing pains”,
• and “it’s all in your head” are just some of them.
Often people get several misdiagnoses before finally being correctly
diagnosed with EDS.  www.ed

Symptoms of EDS:
Although all types of Ehlers-Danlos syndrome affect the joints and many also affect the skin, features vary by type and severity. An unusually large range of joint movement, hypermobility, occurs with most forms of Ehlers-Danlos syndrome, particularly the HEDS (hypermobility) and CEDS (Classical) types. Below is a listing of symptoms that persons with EDS often have. These symptoms are broken down according to body systems. This list is not all-inclusive, but include those most frequently encountered.
Not everyone with EDS has them all and if you have some of them you
may still not have Ehlers-Danlos Syndrome.

Joints:

• Different types of EDS have differing degrees of joint problems.
Joint dislocation and incomplete dislocation called subluxation is
common and recurrent.
• Spontaneous easy reduction or replacement of the finger digits
and shoulders occurs.
• Hypermobile joints cause pain, and sometimes the "cracking" or
"popping" of them feels like it relieves the pressure.
• ‘Pes planus’ or being flatfooted is common and feet can flatten
even more as one ages.
• EDSers can develop osteoarthritis earlier than typical, and they
often have difficulty or pain walking. They can appear klutzy.
• Some EDSers’ hands collapse from the pressure of a simple
handshake. It is difficult to write, and often finger splints help a
great deal.
• Cervical (neck) instability occurs in some types, and some people
may have trouble holding up their head.

• Another frequent joint problem is fluid effusions into the knees,
ankles and elbows, primarily in Classical or Kyphoscoliosis types.
(effusion: The escape of fluid from the blood vessels or lymphatics into the
tissues or a cavity)

• In the Kyphoscoliosis type, many infants have severe muscle
hypotonia (floppy babies), generalized joint laxity and scoliosis at
birth, or develop a progressive scoliosis (a curvature of the spine)
within their first year of life.

• With Vascular EDS, joint hypermobility may be limited to the small
joints of the feet and hands or may be very lax all over. As with
other types, VEDS patients often are first diagnosed as
hypermobile, only later learning that they have VEDS!

The range of hypermobility differs greatly among EDSers, even within types. The loose joints throughout life are unstable, prone to subluxation and dislocation, cause chronic pain and early-onset arthritis. Some people are only mildly affected by their EDS; others are completely debilitated.

Orthopedic procedures to stabilize or improve the joint's function
sometimes put more than expected strain and stress on adjacent joints, leaving many EDSrs disappointed with the results.

So your back, hips, shoulders, knees, 
elbows, and other joints go out 
more often than you do, you might have EDS

 Skin:

General EDS skin traits include:
• Easy bruising, delayed wound healing, differing types of scarring.
• Thinner skin than normal, especially in the Vascular type.
• Those with VEDS have translucent skin where the blood vessels
below are clearly visible.
• Soft, velvety skin that is fragile and sometimes highly elastic
(stretchy) is found, especially in the Classical type.
• Classical type EDS may experience wounds that split open with
little bleeding and leave scars that widen over time to create
characteristic shallow "cigarette paper" scars.
• Surgical incisions may present problems with healing, with stitching
EDS skin sometimes described as "like sewing butter." often
requiring sutures being closer together and left in for a longer time
than usual.
• With severe CEDS, even just leaning on the table with your elbows
can cause the skin to split or may have molluscoid pseudotumors
on elbows and knees. (molluscoid pseudotumors are small, spongy tumors consisting of fat surrounded by a fibrous capsule found over scars and pressure points).
• Skin that sags and wrinkles is characteristic of the Dermatosparaxis type of EDS. Extra (redundant) folds of skin may
be present as affected children get older.
• Skin hyperextensibility to some degree occurs in all types of EDS
except Vascular.
So your skin has so many bruises 
people think you earn your living as a 
boxer, you might have EDS. 

Cardiovascular:

• People with EDS tend to have low body temperatures, may have
trouble controlling their body temperatures when exposed to heat
or cold, and many have blood pressure problems.
• Some have dilated aortic roots, incompetent heart valves, and
autonomic dystonia or POTS (a syndrome where you have wide
and serious blood pressure swings with position changes).
• Many people with EDS bruise very easily and often severely. It can
be difficult for a medical professional to "feel" their pulse.
• Mitral valve prolapse is not a sign of EDS, though someone with
EDS may have MVP; it is not diagnostic for this syndrome.
In some types, arteries including the aortas are very fragile and can
rupture causing a medical emergency.
Note: IV (intravenous) access and even sometimes simply drawing blood for testing may require multiple attempts; using a "butterfly" needle and syringe is much more successful than the use of a vaccutainer which draws the blood rapidly by the use of suction. People with this concern must use extreme care and inform their healthcare providers of these possibilities.

Neurological Symptoms:
• Poor balance, severe headaches including migraines .
• Decreased deep tendon reflexes.
• Intracranial vascular abnormalities.
• Brain "fog", a sense of not being present; absence of focus or a
lack of clarity
• Spinal stenosis (narrowing of spinal column) and/or scoliosis.
Chiari malformation (the brain tonsils protrude down through the
forum at the base of the brain) occurs in some EDS patients.

So you had a school report card 
that said you were fidgety, 
uncoordinated, lazy, under-developed, 
and a complainer, you might have EDS. 

Dental:

• Half of all EDS patients have a hypermobile tongue, and are able
to touch at least the end of their nose with it easily.
• A high palate and crowded baby and adult teeth are common,
even though many EDS patients have smaller than normal teeth.
The high palate and smaller teeth can make fitting dentures very
difficult even when explained to the dentist prior to the dentures
being made.
• Pre-molar and molar teeth often have high cusps and deep fissures
with root problems, and enamel hypoplasia can cause decay and
possible early extractions. Sometimes teeth actually crumble when
losing the enamel.
• Patients with Classical type offer suffer with juvenile periodontal
disease. All EDSers are cavity prone, and have increased bleeding
from anywhere in the oral cavity due to the fragility of tissues.
Braces can cause problems as they can damage the gums and
tongue while moving teeth quickly.
• TMJ (tempomandibular joint) pain and clicking occur in about 30%
of the general population, and about the same incidence occurs in
EDSers. Often if in a dental chair with your mouth open for an
extended period of time, the joint will repeatedly sublux. Taking a
pillow so you can prop your hand up to support your jaw during
the procedure will prevent it from happening and also reduce your
pain level from TMJ.
• Studies have proven that lidocaine (a local anesthetic used during
dental procedures) often works poorly or not at all with EDS
patients.
• Some people with EDS complain of always feeling like there is a
lump in their throat when swallowing, and often have other
swallowing and voice problems.

So a dentist ever gave you so much 
Novocain that his thumb was 
numb, and you could still feel 
everything, you might have EDS! 

GI system:

Gastrointestinal complications of EDS run literally from one end to the other. Frequently EDSers suffer from reflux and GERD, stemming from an incompetent esophageal sphincter that allows stomach acid to backflow up the esophagus and cause burns in it. Diverticula have been seen throughout the G.I. tract.
• Tissue extensibility and laxity can also cause lack of contraction of
the stomach, causing food to not move down into the intestines.
• Megacolon and rectal prolapse may also occur, primarily in
childhood but megacolon is also seen in adults.
(Megacolon is an abnormal dilatation of the colon (a part of the large
intestines) that is not caused by mechanical obstruction. The dilatation is often accompanied by a paralysis of the peristaltic movements of the bowel.)
• Irritable bowel syndrome is a common co-diagnosis. Constipation
can result from the flaccidity of the large bowel, more water being
pulled from the stool the longer it remains in the colon, and from
pain medications.
So your favorite foods are your 
digestive system’s LEAST favorite foods, 
you might have EDS.

Eyes:

An EDSer may have many different eye problems depending on the type of Ehlers-Danlos they have including blue sclera, microcornea (very small cornea), epicanthic folds, and wide-spaced eyes. Other common problems are:

• Many EDSers are photophobic, some squint causing an "angry"
appearance and angiod streaks.
• Loose tendons and ligaments around the eye create hard working
muscles that get tired. Strabismus is the medical terms for eye
conditions commonly called by these various names: eye turns,
crossed eyes, cross-eyed, wall-eyes, wandering eyes, deviating
eye.
• Myopia (near-sightedness), astigmatism, and early presbyopia (a
vision condition in which the crystalline lens of your eye loses its
flexibility, making it difficult to focus on close objects.) occur often
in EDS patients.
• Dry eyes are a common and uncomfortable problem.
• Other EDS related problems are detached retinas and ectopia
(displaced) lenses.
• Persons with Ehlers-Danlos syndrome should see an
Ophthalmologist annually so the internal eye can be checked for
retinal and lens problems among other things. This is not an O.D, a
Doctor of Optometry, but an MD with a specialty in eye issues.

Even during an eye exam, the exam itself can cause vertigo, nausea and headache feeling much like carsickness in some people.


So you change your eyeglass prescription
more often than your wardrobe, you might have EDS! 

Pain:

Pain with Ehlers-Danlos syndrome can range from none to chronic
debilitating pain. It is subjective, individual, and different for each of us. For many patients, this is the worst symptom of all! Causes of this pain can be repeated trauma of constant instability from recent subluxations and dislocations as well as degenerative joint disease. Sometimes poor posture brought on by lax ligaments and weak abdominal muscles cause increased pressure on the spinal joints. Some with EDS do not have pain; others develop it later in life, and others begin to suffer severe pain as children.
• Many things are useful in treating EDS pain such as heated pools
(92-94 degrees), gentle stretching, walking (if your joints allow),
and emotional support that recognizes the degree of your pain
and is non-judgmental.
• Occupational Therapists who make splints and assess what you
may need may help to make daily life easier. Heat and cold packs
help a lot. Always use cold for the first 24 hours after an injury to
decrease swelling and limit bleeding into the area, and then switch
to heat.
• Other possibly helpful things are yoga, relaxation therapy,
massage, acupuncture or acupressure, diversion, TENS units and
chiropractic maneuvers by a knowledgeable chiropractor.
• Common pain management problems are related to medications
either in a too low a dose or prescribing the wrong medication,
overemphasizing risks, using a "cookbook" approach, patients
refusing helpful medications because they worry about addiction,
and doctors afraid of prescribing because of their
misunderstanding of the DEA laws.
• Often pain is undertreated in children, the elderly, and minorities.
Less than 2% of all chronic pain patients (not just EDS patients)
using pain medications correctly for pain become addicted. One
can become dependent, but can be easily weaned off narcotics in
a short amount of time.
• Medications often used with EDS are: muscle relaxants, NSAIDS,
steroids, lidocaine patches, antidepressants, narcotic and nonnarcotic pain medications. Remember that over 4,000 mg. of
Tylenol daily causes liver damage. Different combinations of
medications work for each individual.
• Pain can be completely debilitating and keep you from needed
sleep. Often family and friends don't believe you ... the worst part
of all.

So you have days when you need a 
nap to rest up from the effort of 
getting out of bed in the 
morning, you might have EDS.

Emotional Effects of EDS:

Should either physical disability or chronic debilitating pain make your life feel destroyed, feelings of worthlessness and profound depression may set in; often talking to a counselor or medical professional will help. Regrettably, a tragedy occurs when we not only have to contend with no longer being able to do the things that we have loved doing, but also has to battle for family and friends' belief, respect and understanding. It appears that everyone with an invisible disability sadly experiences this.

While someone with EDS is mourning their loss of ability and freedom, others often accuse them of just being lazy, malingering, or becoming an addict to the pain medications that allow them to live their life. Because of this, we should not confuse their endeavors to live life and be positive with assuming they are feeling well or doing better.

 Knowing you have EDS doesn't suddenly make things worse for you
physically, but may allow for better physical management, and ideally
allow for the prevention of any real problems, even if none exist
currently. So knowing you have it is not necessarily a bad thing.
Personal doubt about one's mental and physical abilities can add to the fear that others can't possibly believe or understand what you're going through. Inability to cope with daily tasks or mental confusion can have a demoralizing effect.

 But there is hope and help. 
You can join EDNF and learn how 
to help yourself, your doctor 
and your future. 
You are not 
alone. 


So you are searching for knowledge, learning about EDS and educating others, you might have EDS!

Please go to the following site for more information:
 http://www.ednf.org/index.php?option=com_frontpage&Itemid=1

Wednesday, May 22, 2013

The First Time EDS Was Recognized....A Long Time Ago!




A syndrome with a history

As early as 400 BC Hippocrates noted that Nomads and Scythians were lax of joint and had multiple scars. The syndrome can also be diagnosed in the Spanish sailor George Albes who was infamous for being able to stretch the skin on his chest out to arm's length. Albes was presented by the Dutch surgeon, van Meekeren, to a group of senior physicians at the Academy of Leiden in 1657.

The first complete description of this condition was given by A. N. Chernogubow in 1892 when he presented two patients at the Moscow Dermatological and Venereologic Society. One of them was a seventeen years old boy who suffered from recurrent joint dislocations and cutaneous nodules, his skin was hyperextensible and fragile and he had multiple scars resulting from minor injuries. Chernogubov accurately diagnosed that the clinical manifestations were caused by an abnormality of the connective tissues. However, the article written by Chernogubov did not come to the notice of Western Europe at that time. The disorder still carries his eponym in Russia.

In 1899 Edvard Ehlers spoke at a clinical meeting of the Paris Society of Syphilology and Dermatology. The patient he presented was a 21 years old law student from the Island of Bornholm in the Baltic sea. This patient gave a history of late walking and frequent subluxations the knees. He had suffered many haematomata on minor trauma, with the formation of discoloured lesions on the elbows, knees, and knuckles. In addition, he had extensible skin and lax digits.

In 1908 Henri-Alexandre Danlos gave a presentation to the same Society. This boy had lesions on his elbows and knees and had been presented to the same Society 18 months previously by Danlos colleagues, François Henri Hallopeau (1842-1919) and Macé de Lépinay, with the diagnosis of juvenile pseudodiabetic xanthomata. At the presentation, Danlos disagreed with the original diagnosis and drew attention to extensibility and fragility of the patient's skin. He stated that the lesions over the bony prominences where posttraumatic 'pseudo tumors' in a patient with an inherent defect which he termed 'cutis laxa'.

In 1936, Frederick Parkes-Weber suggested that the disturbance should bed named Ehlers–Danlos syndrome.

Information taken from the Internet

Monday, May 20, 2013

Downward Slanting Eyes Can Be A Marker In Ehlers-Danlos Syndrome (Scroll Down To See a Picture of My Great Great Grandmother and Me). Ehlers-Danlos Syndrome Can Cause Several Eye Problems

My eyes are either too dry or too watery or blurry or bloodshot looking and many days than not just flat out painful. I see all kinds of floaters, flashes of lights and things or people that I think are moving in front of me when I am alone.... that could push us into another issue, just kidding, but all of these things going on with my eyes, while normal for most people, are more than likely due to having Ehlers-Danlos Syndrome.  

This is a very interesting article from Dr. Diana Driscoll a Therapeutic Optometrist, Optometirc Glaucoma Specialist
You can find lots more information on her website:
www.prettyill.com


Ocular Symptoms Associated With Ehlers-Danlos Syndrome


  • Blurred vision that comes and goes; difficulty in accommodation
  • Diplopia (double vision) – out of one eye, or with both eyes open
  • “Photophobia” (light sensitivity)
  • Complete, or almost complete, loss of vision in one eye that lasts a few minutes; migraine auras, scintillating scotomas
  • Dry eyes
  • Tunnel vision
  • Floaters (EDS patients have more floaters than the general population.)
  • Flashes of light or a curtain over their vision
  • Vision that is not fully correctable with glasses or soft contact lenses.  (Doctors should perform corneal topography on all patients with unexplained blurred vision.)
  • Myopia (nearsightedness) that increases very quickly
  • Doctors and EDS patients must not assume that their symptoms are always due to their EDS and are therefore unactionable.  For example, even among the EDS population, the number one cause of fluctuating vision is diabetes.
By: Dr. Diana Driscoll
Therapeutic Optometrist
Optometric Glaucoma Specialist

There is an amazing amount of collagen in the eye (80% of ocular structures), but relatively, a surprising lack of vision threatening Ehlers-Danlos Syndrome (EDS) related effects.  EDS patients often manifest numerous ocular symptoms.  It is important to understand which symptoms may be indicative of an urgent condition and which are merely annoying. Additionally, it can be difficult to know when a symptom is EDS related, or is an indication of a non-EDS condition. 
This summary should help to guide both patient and doctor with many pieces of the ocular puzzle, guiding both toward conservative, but not unnecessary treatment and testing.1

An incredible 27 different genes are responsible for making the collagen in the structures of the eye.2  The category of EDS that most greatly affects the eye is the rare Type VI- Kyphoscoliosis Type.   In this type, there is a lack of Lysyl Hydroxylase, making the eye structure weak.3 Thus, the eye can perforate with very little trauma.  Fortunately there are only about 60 reported cases of the Kyphoscoliosis Type VI worldwide.4
     The following are common ocular signs, characteristics and symptoms for EDS patients.  Some patients will show many of these signs and symptoms and some will show few, if any.
       Dr. Diana Driscoll

High Myopia

     Also known as near-sightedness, myopia causes the patient to have more difficulty seeing objects at a distance than objects up close.  Myopia is common in EDS and non-EDS patients.  Myopia is typically due to a slightly elongated eye or a very steep cornea, or both.5  In EDS, however, the corneas are often found to be fairly flat, meaning that the near-sightedness is due primarily to elongation of the eye.6

Retinal Detachments

      EDS patients are prone to myopia and elongated eyes due to the stretching of the collagenous sclera.  The retina (neural tissue) doesn’t stretch with the sclera but rather gets “pulled along for the ride” and can become thin resulting in retinal holes, tears, staphylomas, retinal degenerations and detachments.  Dilation of the eyes is recommended annually, or any time the patient notices a sudden increase in floaters, flashes of light (usually out to the side of the vision), or immediately if it seems as if a curtain is coming up over one eye.  These can be symptoms of a retinal detachment and may need to be treated on an urgent basis.7

Keratoconus

       In this condition, the cornea (on the front part of the eye)  bulges outward in a cone shape, and gravity pulls the cone downward, blurring the vision and making it difficult to see well with glasses or soft contact lenses.  Rigid contact lenses are usually tolerable for many years, but about 40% of keratoconic patients will eventually need a corneal transplant as their rigid contact lenses become less comfortable with progression of their keratoconus.  Some new research (discussed below) may radically reduce this percentage soon.
     Early symptoms of keratoconus include vision that just doesn’t seem as clear to the patient as it should be – even with use of new glasses or soft contact lenses.  It is usually worse in one eye than the other. 
     Corneal topography will indicate steepened corneal curvature, especially on the inferior cornea. If topography indicates keratoconus this is a prime opportunity to screen the patient for EDS.   This screening need not be extensive, but a quick Beighton scale, understanding that hypermobility is more common in the metacarpo-phalngeal and wrist joints with keratoconic patients, is a great place to start.8
     In keratoconic patients, one eye is usually able to “cover for the other eye” for months to years, thus no treatment beyond glasses or contacts may be necessary during this time.  When both eyes are involved to the point that the patient is unable to see what he/she needs to see, then other options are explored.  This usually begins with gas permeable lenses, which may remain comfortable for the patient for many years.

Treatment of Keratoconus

     If the gas permeable lenses designed for keratoconus are not comfortable for the patient, one of the new generations of contact lenses with a soft skirt and a rigid center are becoming increasingly popular as manufacturers are learning how to avoid the previously common splitting of the contact lens between the rigid portion and the soft portion. Synergeyes™ lenses are one of the most popular brands.  Scleral lenses (rigid lenses that cover the entire cornea and overlap onto the sclera) are making an impressive comeback with increased comfort for the patient, as opposed to the first scleral lenses from decades ago.
     If these lenses are not tolerable, or if their comfort is unacceptable at any time, other options can be considered, including:
  • Intra-corneal ring segment inserts, such as “Intacs™”.  These are small semi-circles that are inserted into the middle layer of the cornea, usually on the inferior portion of the cornea and can often return the patient to acceptable vision with glasses or contact lenses.  They are also removable should the need arise.
  • Corneal transplantation (or grafting):  This may involve a penetrating keratoplasty (a full thickness transplantation or graft) or a lamellar keratoplasty (a partial thickness transplantation or graft).  These transplants are generally successful (over 90%) primarily because the cornea does not have a vascular system which would normally transport the cells to reject a transplant.  It is possible to see a graft begin to develop keratoconus, but this generally doesn’t begin to occur until at least 18 years after surgery.9
  • There is an exciting new discovery that could change the prognosis and lives of keratoconic patients everywhere.  Researchers have learned that by rinsing the cornea with riboflavin drops for about 30 minutes, then shining UV-A rays on the cornea for about 30 minutes (CR3) the collagen fibrils of the cornea develop stronger cross-links, strengthening the cornea.  This corneal strengthening is resulting in the halt and even the reversal of keratoconic progression.  The implications for the treatment of Type VI EDS, and the use of riboflavin and UV-A on the skin is also enticing for most researchers, and we eagerly await testing.10
  • Please be aware that patients with EDS, and especially those with signs of keratoconus, are not candidates for radial keratotomy or LASIK refractive correction.  Because of the abnormal structure of the collagen in the cornea, the patients are more prone to poor healing, corneal ectasias (bulging of the corneas after surgery), and a disappointing result.  Orbscan and pachymetry results usually indicate areas of corneal thinning (prior to surgery).
     Although previous studies have indicated that the population of EDS patients rarely shows keratoconus, the corollary indicates the opposite – approximately 40% of keratoconus patients have been shown to have EDS.11

Blue Sclera

     This is a fairly subjective finding, but EDS patients tend to have thin scleras (the underlying “white part” of the eye).  Thus, the darker underlying layer, the choroid, shines through with a blue- grey tinge.  Most children normally have bluish scleras, but as we age the sclera thickens.  This is easiest to see in a very dim room with a bright light shining on the temporal cornea (while the patient looks nasally).12

Lens Subluxation

     This is most commonly seen in Marfan’s syndrome or in EDS patients with marfanoid phenotype (appearance), or those with EDS Type VI.  The intraocular lens of the eye is held in place by thin zonules that can break easily in Marfan’s and cause the lens to subluxate.  If this happens, the patient may notice double vision out of that eye.  The lens is surgically removed with as little trauma to the eye as possible.13

Angioid Streaks

     Angioid streaks can be seen during ophthalmoscopy (best seen with the binocular indirect ophthalmoscope), and are seen in some EDS patients and patients with other conditions such as thalassemia, sickle cell anemia, Paget disease of bone, tumoral calcinosis, hyperphosphatemia, lead poisoning and PXE - pseudoxanthoma elasticum).14
     Angioid streaks can be easily overlooked if the eye is examined with too much magnification.  Angioid streaks appear as mud cracks in the fundus.  These are actually breaks in one of the layers of connective tissue in the eye (Bruch’s membrane).  If angioid streaks are seen on examination, the search should begin for a systemic cause.15  Generally, the streaks themselves are harmless.  They should be monitored on an annual basis to check for abnormal blood vessel formation in the cracks which may need to be treated with a laser.  Otherwise, they are mainly an indication of a systemic irregularity such as EDS, causing the condition.16

Epicanthal Folds

     Epicanthal folds are often recorded in the literature as a frequent sign of EDS, however a study of the literature reveals that “epicanthal folds” are often misdiagnosed, and true epicanthal folds are actually fairly rare in EDS. 
     An epicanthal fold is a fold of skin that comes down across the inner angle (canthus) of the eye. The epicanthal fold is fairly common in children with Down’s Syndrome, and many healthy babies and toddlers have epicanthal folds that they typically outgrow by the age of 3-5 years.  True epicanthal folds sometimes make it appear as if the child has “crossed eyes”.  This is easily differentiated from esotropia by gently pinching back the skin near the nose, and verifying that the child’s eyes are tracking properly.    
     What is common in the eyes and lids of EDS patients, however, is redundant skin on the upper lids, easy eversion of the upper lids and downward slanting eyes (the temporal portion of the eyelids slant down a bit).   Again, perfectly harmless, but this appearance can be another piece of the puzzle for the doctor.17     


 This a picture of me and my Great Great Grandmother. We both have downwards slanting eyes. My Great Great Grandmother had and so do I Ehlers-Danlos Syndrome.




                                    

Dry Eyes

     Dry eyes are a common finding in EDS patients (and not uncommon in non-EDS patients).  There are numerous effective treatments and medications for this symptom, which can become debilitating in some patients if left untreated.
     First, the eye doctor will need to determine why the eyes are dry (and ironically, the patient’s main complaint may be watery eyes – due to reflex tearing from the corneal dryness.  Unfortunately, reflex tears do not contain all three layers of tears and thus provide no therapeutic benefit to the patient). 
      Normal tears that cover the corneal surface are comprised of three basic components:
1.   The lipid, or oil component, which is the outer layer of the tear film and helps prevent the lacrimal layer beneath it from evaporating or overflowing onto the lower eyelid.
2.   The lacrimal, or watery component, provides the bulk of the tears and contains salts, proteins, and an enzyme called lysozyme that protects and nourishes the eye.
3.   The mucoid, or mucus component - the bottom (base) layer of tears. This component tends to cause the tears to adhere to the eye and prevents evaporation.
     All three components of the tears in proper balance, are necessary for effective lubrication.
     A complete dry-eye work-up is needed to determine the cause of the dryness, and thus the effective treatment.  Fluorescein, together with other dyes (lysamine green or rose bengal) will indicate the extent of cell dryness and damage.  A Schirmer Test can measure the lacrimal (“watery”) tear production, usually performed with anesthetic over 5 minutes.

Treatment of Dry Eye Syndrome

Treatment of dry eye syndrome primarily consists of one or more of the following; medications, nutritional supplements, artificial tears and punctal occlusion.  Dry eye therapy must be tailored to the specific cause of the patients symptoms.  Often a stepwise approach for dry eye treatment is beneficial. 

Medications

The prescription medication Restasis can help eyes increase tear production, and a topical steroid drop can reduce the inflammation that often results from a chronic dry eye (this is usually used initially, then tapered and discontinued as symptoms improve).  Equally important is the avoidance of medications that can cause or exacerbate dry eyes – antihistamines and diuretics, for example.
     Another treatment option is the use of Lacriserts® -  tiny discs made of hydroxypropyl cellulose that are inserted by the patient into the inferior cul-de-sac of the lower lid.  These small discs “melt” throughout the day, providing a continuous source of moisture for the patient.

Ointments

     Ointments at night-time can be used (unpreserved ointments are preferred), and are especially helpful if the patient does not sleep with their eyes completely closed (“nocturnal lagophthalmus”, a fairly common condition).  It is also recommended that the patient sleep without their ceiling fans.

Essential Omega 3 Fatty Acids

    A critical aspect of dry eye treatment involves the use of the essential fatty acids also known as the Omega 3 fatty acids.  Eicosapentaenoic acid and docosahexaenoic acid, more commonly known ad EPA and DHA are the essential fatty acids that are known to improve the tear break up time by making the tears oily, thus decreasing their evaporation rate.

Punctal Occlusion

     Punctal plugs are effective in retaining the patient’s own tears.  These silicone plugs are (painlessly) inserted into the lower, and sometimes the upper and lower puncta (the opening of the tear drain, if you will).  It is similar to putting a cork in the drain.  These plugs are also removable, should they cause the retention of too many tears.  It is generally not advisable for EDS patients to have their puncta surgically closed because of the risk of poor healing, and the common reopening of the surgically closed puncta.
     There is no evidence in the literature that indicates a loss of reflex tearing with EDS.18Next: Continue to posterior staphyloma, macular degeneration, glaucoma and more

Glaucoma

     In glaucoma the drainage of aqueous humor (the liquid in the front part of the eye) is inefficient, or the eye produces fluid too quickly to drain effectively.  This causes pressure on many structures of the eye, including the optic nerve.  The damaged optic nerve can result in blindness if not treated.  The most common type of glaucoma is called “primary open angle glaucoma” or “POAG”.  In cases of POAG, the drainage canal for ocular fluid appears to be open.
     A highly nearsighted individual has a greater risk association with POAG, and nearsightedness is more common with EDS. The elongated eyeball, characteristic of nearsightedness, allows a larger optic channel with the optic nerve fiber becoming more susceptible to pressure and injury.19
     Glaucoma can be congenital, for example, when the ducts responsible for fluid drainage fail to form completely. Some infants are born with defects in the angle of the eye that slow the normal drainage of aqueous humor, a condition most often correctable with surgery if discovered early enough.  This is often seen in Type VI EDS, in conjunction with an abnormally small cornea (“microcornea”) and the thin, blue sclera.
     Individuals who have either Ehlers-Danlos syndrome or Marfan's syndrome, a condition characterized by elongation of the bones, appear to have a higher association with glaucoma.
     Treatment for glaucoma (POAG) begins with eye drops and/or pills to lower the pressure.  If the glaucoma is due to a defect in the drainage canal, argon laser surgery is usually indicated to open a few areas for the fluid to drain.  As in any surgical treatment for EDS patients, special care is taken to traumatize the eye as little as possible.20
     Symptoms of POAG don’t appear until it may be too late to save the vision in that eye.  Annual eye exams including routine checks of intraocular pressure (with pachymetry or Orbscan for accuracy of diagnosis) and early treatment when warranted are the best ways to thwart glaucoma and its damaging ocular effects.21

Strabismus

     Strabismus (crossed eyes or eye drifting outwards, upwards, or downwards) can also be found in EDS patients and non-EDS patients.
     Strabismus occurs when the six extra-ocular muscles that control eye movement are not in balance.  Not dissimilar to the loose joints in the EDS patient, one or more of the extra-ocular muscles is looser than the others, resulting in the eye drifting or crossing.
     Extra effort may be needed to keep proper alignment of the eyes, causing eye fatigue.  Multifocal lenses (bifocals or trifocals) can help to balance the muscle activity associated with changing focus from faraway to close up and back to distance.  Prism in prescription glasses can be helpful in directing light to the correct spot on the retina, so that the eyes do not need to work so hard to do so.  Surgical repair of a strabismus may be complicated because sutures may be difficult to place in thinned sclera of EDS, especially in Type VI.  As in any muscle or ligament surgery on the EDS patient, some surgical results may not have lasting effects.22

Macular Degeneration

     The macula is the part of the retina that is used for central vision.  In macular degeneration, loss of proper functioning of the macula results in blindness of the central vision (peripheral vision is usually left intact).  It is the leading cause of blindness in those Americans over the age of 55 years, and it affects over 10 million Americans.
     The cause of macular degeneration is not yet fully understood, but it does appear that EDS patients are more prone to developing this condition.  Macular degeneration can be divided into two types – atrophic (or the “dry” form) and the more damaging “exudative” (or “wet” form).  Because the macula is physically supported by the collagen of the eye and receives nutrients through the network of blood vessels in the area, it is easy to hypothesize how a collagen and/or vessel abnormality could contribute to macular degeneration.  More research will need to be done, however, to effectively treat or prevent this condition
     A major National Eye Institute study, Age Related Eye Disease Study (AREDS), has produced strong evidence that certain nutrients such as beta carotene (vitamin A) and vitamins C and E in conjunction with zinc and Omega – 3 fatty acids may help prevent or slow progression of dry macular degeneration.23
     Until recently the only available treatment to seal leaking vessels in the exudative form of macular degeneration was with laser photocoagulation.24  This was followed by Photodynamic Therapy (PDT) with Visudyne® (a drug injected intravenously and used to help direct the laser to the affected area) and is not suitable for all types of lesions.25
     Recently, it was discovered that there is a protein in the eye which encourages the development of blood vessels.  Given the name "vascular endothelial growth factor" (VEGF), researchers have been working to develop treatments to inhibit VEGF by trapping it or preventing it from binding with elements which will stimulate growth. Chemically synthesized short strands of RNA (nucleic acid) called "aptamers" prevent the binding of VEGF to its receptor.  Presently three types of VEGF inhibitors are in use: Lucentis, Macugen and Avastin. All are given by intraocular injection.26

Posterior Staphyloma

     Because of the inherent weakness of the sclera in EDS, these patients are more susceptible to developing posterior staphylomas.  This is usually seen in conjunction with high myopia.  Binocular indirect ophthalmoscopy or fundus photography are both good screening tools for staphylomas.27

Carotid-Cavernous Sinus Fistulas

     A carotid-cavernous sinus fistula is the rupture of a blood vessel that subsequently bleeds into a sinus cavity and/or some part of the eye. The blood flow can cause serious structural damage to the eye and is considered a true emergency.  Individuals often report hearing their pulse in their temple and having a frontal headache on one side or the other. Sometimes the eye on that side is proptotic (it seems to be more prominent than the other eye) and it can become very red. 28
     Check for carotid-cavernous sinus fistula by placing a stethoscope over the patient’s temple and listen for a 'whooshing' sound. Carotid-cavernous sinus fistulas are more commonly found in the vascular form of EDS, (Type IV), but all types and the normal population are susceptible as well.29Next: Continue to common ocular symptoms associated with Ehlers-Danlos Syndrome

References

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15 Grand MG, Isserman MJ, Miller CW (1987). Angioid streaks associated with pseudoxanthoma elasticum in a 13-year-old patient.  Ophthalmology Feb;94(2):197-200.
16 Gomolin JE (1992).  Development of angioid streaks in association with pseudoxanthoma elasticum.  Can J Ophthalmol Feb;27(1):30-1.
17 Seki M, Iwasaki M, Takei K, Maeda T (1989).  A case of Ehlers-Danlos syndrome.  U.S. National Library of Medicine.  27(1):208-19.
18 Choudhury R, Revenco V, Darciuc R (2009).  Ehlers-Danlos syndrome.  BMJ Case Reports 10.1136.
19 Musch DC, Lichter PR, Guire KE, Standardi CL (1999).  The collaborative initial glaucoma treatment study: study design, methods, and baseline characteristics of enrolled patients.  Ophthalmology Apr;106(4):653-62.
20 Higginbotham, E (1998).  Initial treatment for open-angle glaucoma – medical, laser, or surgical?  Arch Ophthalmol; 116:239-240.
21 Lee D, Higginbotham E (2005).  Glaucoma and its treatment: a review.  American Journal of Health-System Pharmacy 62(7):691-699.
22 Meyer E, Ludatscher RM, Zonis S (1988).  Collagen fibril abnormalities in the extraocular muscles in Ehlers-Danlos syndrome.  J Pediatr Ophthalmol Strabismus :25(2):67-72.
23 Sangiovanni JP, Agron E, Meleth AD, Reed GF, Sperduto RD, Clemons TE, Chew EY (2009).  Omega-3 long-chain polyunsaturated fatty acid intake and 12-y incidence of neovascular age-related macular degeneration and central geographic atrophy: AREDS report 30, a prospective cohort study from the Age-Related Eye Disease Study.  Am J Clin Nutr; 90(6):1601-7.
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