# Mast Cells and Stress



## eric (Jul 8, 1999)

FYI http://66.218.71.225/search/cache?p=mast+c...ssmastcells.pdf


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## kel1059 (Feb 28, 2003)

excellent paper. this differential release of mediators is something that is very important and may help explain why HT can at least make some people feel better. also, very possibly have an inhibiting effect on the release. i would be interested to see any results of HT and IgE allergy relief -- i.e., does HT reduce allergy attacks.i don't deny that stress can activate the mast cells -- i know they can. but just so long as you realize that many things are causing this to happen.my big trigger is mold spores and foods. stress gives me more of a cerebral reaction than a gut reaction.we are all different.


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## eric (Jul 8, 1999)

Molds are a new one for you yes Kel? I have lost count of how many things you have wrong with you, not related to IBS.At an IBS support group a year ago a clinical hypnotherapist was hypnotizing the group and was telling everyone they were in a garden and to feel smell and breathe the air. Some ladies allergies acted up and she began to sneeze and her nose watered.Kel, its emotions and the fight or flight, and you would not conciously be aware everytime of this happening. SO it can be happening without you knowing it. This is very Important to know in IBS!It has to do with homoestasis!Chronic stressors and negative emotions through worry and emotions like anger for one, activates the HPA axis then the fight or flight responce and this sends signals from the brain to the gut that degranulates the mast cells to release toxins onto the nerve cells of the gut, without a pathogen.Right now there is major research being done on this that may help to explain the pain generation and IBS.Kel, your brain and your gut are majorally connected through the CNS and the ENS and the autonomic nervous system and even though the gut can run on its own for the most part the brain is still in charge of many of its operations, including the immune system."Basic Principles -- Brain-GutModerators: Emeran Mayer MD; Robin Spiller MD. Panel: Robin Spiller MD; Jackie Wood PhD; George Chrousos MD; Yvette Tachï¿½ PhD; Lisa Goehler PhD; G.F. Gebhart PhD; Emeran Mayer MD.Click on Titles to View Other TopicsIntroductionOutcomes of Pediatric Functional GI DisordersEpidemiology/Genetic/Behavioral FactorsBrain ImagingEmerging Techniques to Evaluate and Treat Functional GI and Motility DisordersClinical Applications of Diagnosis and TreatmentFunctional GI DisordersGeneral Principles of TreatmentPharmacological TreatmentPsychological TreatmentIFFGD Research AwardsThe brain-gut axis refers to the continuous back and forth interactions of information and feedback that take place between the gastrointestinal tract, and the brain and spinal cord (which together comprise the central nervous system). These interrelated feedback circuits can influence brain processes and bowel functions -- affecting pain perception, thoughts and one's appraisal of symptoms, gut sensitivity, secretions, inflammatory responses, and motility. The brain-gut circuits can be activated by an external or internal factor or stimulus that makes a demand on the system, such as a stressful event, an injury, an emotional thought or feeling, or even the ingestion of food. Symptoms of functional GI disorders may result from a maladaptive response to stimuli at some point within the complex interactions that take place along the brain-gut axis.Basic science is the fundamental approach to understanding how systems work. Basic research takes place in the laboratory and often involves the study of molecules and cells. From this body of knowledge is drawn the means to investigate practical applications and to formulate clinical practices. Translational science converts basic science discoveries into the practical applications that benefit people.One of the more exciting areas of recent research relates to the basic and translational aspects of the effects of stress on inflammation, cytokine and immune modulation, and pain. (Cytokines are a type of protein released by cells of the immune system, which act through specific cell receptors to regulate immune responses.) This series of presentations address three important research areas in the field of functional GI disorders, which have recently attracted considerable attention: the role of immune activation in the gut and the interactions of the gut immune and nervous systems; the role of the central nervous system in the regulation (modulation) of pain perception (nociception); and the emerging field of animal models with relevance for functional GI disorder research. This section demonstrates the rapid progress seen in the last few years in better understanding of basic mechanisms, in particular the neuroimmune interactions underlying symptom generation in patients with "functional" GI disorders.There are immune responses to infections. To defend itself from a foreign substance or invader, such as a bacterium or virus, the body mounts an immune response controlled by the brain. There needs to be a balance between infection and the body's immune response; the immune system needs to turn on and turn off at the right times to destroy the invader but not to the degree that it may harm healthy tissue.Robin Spiller, University Hospital, Nottingham, England began the session by noting the difficulty in separating disorders of structure ("organic") from disorders of function. He noted, "The difference is based on how high the power of your microscope is." This was elaborated upon in his presentation on Post-infectious Functional GI Disorders. It has been observed that IBS-like symptoms, that persist for 6 months to a year or longer, may appear after a bout with an acute infection in the gastrointestinal tract (e.g., food-poisoning). This is termed, "post-infectious IBS." A study by Gwee et al showed that the presence of unusual or amplified life stress at the time of onset of infection increased the chances of developing IBS symptoms. Inflammation persisted in patients with IBS-like symptoms but did not in patients whose symptoms resolved. This suggests that the brain's management of certain stressful stimuli (i.e., psychologic distress) affects the brain-gut system's ability to inhibit inflammation.It has frequently been observed that some individuals with more severe symptoms of IBS have coexisting psychologic distress. Stress has been thought to influence health-care seeking behavior, either by increasing motility, visceral hypersensitivity or inflammation, or by enhancing one's perception of gut symptoms, all of which lead to a greater need to seek care for them. The concept of post-infectious IBS suggests that in some circumstances stress (the biological process by which the body adapts in response to a stimuli) may influence symptoms.An initial response to an infection in the gastrointestinal tract can involve the neurotransmitter, serotonin, which acts as a messenger (mediator) to cells involved with the immune response. Immune cells -- mostly in the blood, but also in the lymphatic system -- enter the infected area and remove the invader. Additionally, the body adaptively removes the infection (e.g., via vomiting or diarrhea -- normal beneficial responses that help the body expel an infecting organism). Persistence of the underlying inflammatory response may lead to post-infectious disorders of function. A variety of neuroimmune responses can lead to intestinal over-responsiveness (sensitization) and other clinical effects.These responses include direct toxicity to nerves that influence intestinal contractions, alteration in gut immune activation, abnormalities of serotonin metabolism, and persisting low-grade inflammation. IBS developing after infective gastroenteritis is associated with subtle increases in enteroendocrine and chronic inflammatory cells in the gut mucosa. The net effect may be to increase serotonin availability in the gut and enhance secretion and propulsive motility patterns. Serotonin antagonists may be beneficial in such patientsNotably, the concept of "post-infectious IBS" has grown to include studies of their application in post-infectious gastroparesis and dyspepsia. 1Major inflammatory responses have not been observed in most IBS patients. However, in some studies subtle changes associated with inflammation have been noticed, such as increased presence of mast cells (a type of immune system cell present in blood and tissue). Jackie Wood, Ohio State University College of Medicine discussed the Effects of Inflammation on the Gut Enteric Nervous System, specifically noting the importance of mast cell degranulation (the release from within the cell of granules, or small sacs, containing chemicals that can digest microorganisms and fight infection).In tissue mast cells accumulate around nerve endings of nerves that contain the neurotransmitter serotonin. The release of substances that can induce activity in excitable tissue (i.e., histamine, Interleukin-1 (IL-1), and bradykinin) by mast cells can affect receptor and neurotransmitter function in the enteric nervous system - the part of the autonomic nervous system that controls function of the gastrointestinal tract. In other words, when mast cells in the intestinal lining empty their contents in response to an infection, they activate nearby nerve endings. In a subgroup of patients, this can have significance in terms of resulting clinical consequences of diarrhea and abdominal discomfort.2Yvette Tachï¿½, University of California Los Angeles discussed Stress and Inflammation. The experience of stress is an adaptive behavior common to all living organisms. The activation of corticotropin releasing factor (CRF) signaling pathway, is the major mediating mechanism involved with the body's stress response system in which gastric emptying is inhibited (with possible loss of appetite) while colonic motor activity is stimulated (producing a loose stool or a sensation of bowel urgency). There is growing evidence that activation of this CRF pathways impacts on inflammation, autonomic nervous system function, immunity, and clinical behavior or illness, all of which may be linked to the pathophysiology of the functional gastrointestinal disorders.While we often talk about how the brain -- influenced for example by arousal and/or psychosocial factors -- can affect immune function, the reverse is also true. Immune activation, following infection for example, can influence brain function. Lisa Goehler, University of Virginia discussed Cytokines and Vagal Afferents: Immune Signaling to the Brain. Cytokines are substances that are produced by white blood cells to regulate certain functions during inflammatory and immune responses. The vagus is a nerve made of both sensory and motor fibers that innervates nearly every internal organ. The gastrointestinal (GI) tract, along with the lungs and liver, is an area of tissue that most commonly comes in contact with microorganisms (pathogens), such as bacteria or viruses, capable of activating an immune response. Cytokine mediators activate neurons that convey messages from tissue to the brain (afferent neurons) through the vagus nerve. The GI tract is richly supplied with vagal afferents that can signal immune activation in the tissue.This process may underlie the mechanism that causes individuals to feel sick. The concept of "sickness symptoms" is not always recognized. The cytokine inflammatory and immune mediators distributed throughout the body (peripheral), which appear to interact through vagal pathways, have systemic effects that manifest as symptoms in the body. (Mediators are substances released from cells to regulate immune responses.) Such symptoms include fever, increased sensitivity to pain, loss of appetite, and decreased desire for social interaction. The process may provide the basis for a role of the vagus as an interface between the site of the immune response and the brain that results in symptoms of altered mood, including anxiety or depression, that are sometimes associated with gastrointestinal disease.4Jerry Gebhart, The University of Iowa discussed the CNS Modulation of Visceral Nociceptive Responses. The central nervous system (CNS) is composed of the brain and spinal cord. The brain interprets and influences our perceptions of the pain sensation signals transmitted from the gut (visceral nociceptive responses) to the spinal cord and then to higher centers. Several structures in the brain (periaqueductal gray, dorsolateral pons, and rostroventral medulla) can facilitate or inhibit signals sent to the CNS and influence the perceived discomfort, or even whether the signals are experienced as pain. Inflammation of the bowel can produce increased sensitivity to pain or enhanced intensity of pain sensation (hyperalgesia) via increased activity of certain cells (for example, those that contain nNOS) in these higher brain modulatory centers.5To close the Brain-Gut sessions, Emeran Mayer, University of California Los Angeles discussed Evolving Animal Models of Visceral Hypersensitivity. In contrast to most other disorders of the digestive system, functional disorders of the gut continue to be defined by symptom criteria rather than by biological markers. Realistic animal models of functional gastrointestinal (GI) disorders in which to test hypotheses have not been available until recently. While it is unlikely that there will ever be an animal model to replicate all complexities of the human functional GI disorders, animal research is likely to help us understand some of the key underlying mechanisms responsible for symptom generation. This includes over-responsiveness of central stress circuits to visceral and psychological stimuli, resulting in altered autonomic responses (motility, secretion), increased pain sensitivity (visceral hypersensitivity) and possibly altered immune function of the gut. Future studies with genetically altered (i.e., transgenic) mice that become models for studying specific human diseases and their treatments may further increase our understanding of these mechanisms.6 http://www.iffgd.org/symposium2003brain-gut.html


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## ohnometo (Sep 20, 2001)

Also, along with stress............Many Foods Contain Histamine Or Cause The Body To Release HistamineHistamine is a natural substance produced by the body and is also present in many foods. It is released by the body during times of stress and allergy.In an allergic response, an allergen stimulates the release of antibodies, which attach themselves to mast cells. When histamine is released from the mast cells it may cause one or more of the following symptoms:Eyes to itch, burn, or become watery Nose to itch, sneeze, and produce more mucus Skin to itch, develop rashes or hives Sinuses to become congested and cause headaches Lungs to wheeze or have spasms Stomach to experience cramps and diarrheaThis chemical (vasoactive amine) is able to create such havoc with the many body functions because it is contained in almost all body tissues. The main body tissues include the lungs, skin, intestinal mucosa, mast cells, and basophils.The release of histamine can be induced by almost any allergen. Examples include inhalant allergens, drugs, chemicals, insect venoms, and even some foods.Histamine in FoodsThere are many foods that contain histamine or cause the body to release histamine when ingested. Histamine in food may be responsible for some cases of food intolerance.Histamine Rich Foods Include:Anchovies Avocados Beer Canned Foods Cheeses Cidars Eggplant Fermented Beverages Fermented Foods Fish Herring Jams and Preserves Mackerel Meats Processed Meats Salami Sardines Sauerkraut Sausage Some Oriental Foods Sour Cream Spinach Tomatoes Tuna Vegetables Vermouth Vinegars Wines Yeast extract YogurtHistamine Releasing Foods Include:Alcohol Bananas Certain Nuts Chocolate Eggs Fish Milk Papayas Pineapple Shellfish Strawberries TomatoesHistamine PoisoningAt times the ingestion of high concentrations of histamine may lead to histamine poisoning. It is also known as Scombroid Poisoning. High levels of histamine occur in spoilage of foods such as fish products.


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## Lauralee (Jan 4, 2002)

> quote: i.e., does HT reduce allergy attacks


Just my own experience...I suffer from "severe and extensive" allergies, as my allergist once put it. I did IBS based hypnotherapy, finishing up almost two years ago. I have to say that last spring (spring is when my alllergies are at the worse) I had much fewer problems than usual. I needed my allergy eye drops only twice all spring whereas in the past I needed them almost every day. Could it be coincidence? Sure, it could, but there also could be a connection between the two. I am anxious to see how I react this spring!


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## kel1059 (Feb 28, 2003)

donna,thanks for posting that information. a lot of those foods are my biggest triggers.i think it is easy to see that stress and foods can be triggering these chemicals.i am going to look deeper into the various ways that we can try and desensitize these mast cells.


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## ohnometo (Sep 20, 2001)

KelHave you read any information about cromolyn sodium. I believe it is a mast cell stabilizer of known effectiveness...I dont know to much about it but I have read something about it here on the board before..


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## kel1059 (Feb 28, 2003)

> quote: Just my own experience...I suffer from "severe and extensive" allergies, as my allergist once put it. I did IBS based hypnotherapy, finishing up almost two years ago. I have to say that last spring (spring is when my alllergies are at the worse) I had much fewer problems than usual. I needed my allergy eye drops only twice all spring whereas in the past I needed them almost every day. Could it be coincidence? Sure, it could, but there also could be a connection between the two. I am anxious to see how I react this spring!


very interesting. thanks.


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## kel1059 (Feb 28, 2003)

i remember MNL talking about it a lot, but he made it sound as though the effects were short lived. that is why i never pursued it, but maybe it has long lasting effects elsewhere in the body.i think i am going to investigate this.


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## poet (Nov 17, 2003)

I think his position would be that mast cell changes can be permanent? If we're talking about mast cells we need someone who knows about them. I would suspect this works in much the same way serotonin changes change brain cells reception.tom


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## kel1059 (Feb 28, 2003)

> quote:I would suspect this works in much the same way serotonin changes change brain cells reception


yes and recent evidence suggests that these changes could be problematic.i believe that he only made the claim that cromylin was only prophylactic.


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## poet (Nov 17, 2003)

let's base this on what MNL says. I'll see if I can contact him.tom


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## bonniei (Jan 25, 2001)

http://www4.infotrieve.com/newmedline/deta...ndrome&count=20 The average time the subjets in the study had iBS was two years which makes me think that mast cell changes were permanent.in terms of serotonin the enterochromaffin cells which conntain serotonin are important. Apparently they can predict post-infectious IBS. http://www4.infotrieve.com/newmedline/deta...ndrome&count=20 i do wish MikeNL was around. I hope you can contact him, tom. i miss him.


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## bonniei (Jan 25, 2001)

From the first paper'Once stimulated, mast cell products may encourage further proliferation, resulting in a *self-perpetuating increase in mast cell numbers* long after the initiating event has subsided. In IBS, we propose that the mast cell may be an important mediator in a complex interaction between a physiological event (gut insult, inflammation, tissue injury, nerve injury), the nervous system and psychological factors (stressful events, emotions). 'As to how they act - from the first paper-"Potent chemicals derived from mast cells, including histamine, 5-HT, platelet activating factor, prostaglandins, cytokines and leukotrienes, may be implicated in the generation of IBS symptoms via their effects on enteric muscle and nerve function"


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## kel1059 (Feb 28, 2003)

i strongly suspect that ibsacol is playing a strong role in stopping some of the inflammatory prostaglandins and leukotrienes from either manufacture or release from mast cells. the best indication is my much lowered asthma response and the fact that i no longer have to take an anti-seizure drug after 3 to 4 weeks on it.i have heard that quercetin can help to control and stabilize the mast cells. i took 1000mg for 6 months but it is hard to tell if it did anything. i have read that 4000 to 6000 mg may be needed.


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## bonniei (Jan 25, 2001)

Quercetin is in a class of flavonoids call flavonol. Its usage is inversely correlated with chronic coughs. Don't know the dosage though


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## poet (Nov 17, 2003)

Interesting, this -------------------"Potent chemicals derived from mast cells, including histamine, 5-HT, platelet activating factor, prostaglandins, cytokines and leukotrienes, may be implicated in the generation of IBS symptoms via their effects on enteric muscle and nerve function"-------------------seems to indicate that mast cells determine serotonin (5HT) but I'm sure it's not that simple.Mike's usually busy when I contact him but maybe I can get him to drop in. Why not send him a PM yourself?tom


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## bonniei (Jan 25, 2001)

I missed that. I think you may be right, tom


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## poet (Nov 17, 2003)

actually it's possibly exciting if hypnosis->mast cells->5 HT?tom


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## bonniei (Jan 25, 2001)

Yes. i am afraid i don't know much about it.


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## poet (Nov 17, 2003)

guess we'll have to wait for Mike to expain it?tom


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## bonniei (Jan 25, 2001)

Yes do write to him.


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## bonniei (Jan 25, 2001)

Hopefully he will be able to pinpoint us to landmark papers.


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## Mike NoLomotil (Jun 6, 2000)

A voice from the past appeared in my eamil!Hola, Tom Donna and rest of Ya'll...lemme see what ya got here be right back after I give 'er a quick readMNL


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## Mike NoLomotil (Jun 6, 2000)

Ok seems a whole bunch of chat and Q's about the infernal issue of mast cells and IBS etc....Some key questions/issues appeared to be:"KelHave you read any information about cromolyn sodium. I believe it is a mast cell stabilizer of known effectiveness...I donï¿½t know to much about it but I have read something about it here on the board before..Donna""I think his position would be that mast cell changes can be permanent? If we're talking about mast cells we need someone who knows about them. I would suspect this works in much the same way serotonin changes change brain cells reception."let's base this on what MNL says. I'll see if I can contact him."tom _________________________________OK I have been forced to become even more direct in manner as the demands of the business have grown in the past 6 months....much activity and growth limits time for interfacing with fellow Gut-Busters...a lot of people not buying Immodium anymore!OK, So, first a very very surface-scratching background on mucosal and cellular immune function in the gut and these funky mast cells and other stuff...if you know me expect typos as I still use 2 fingers and still do not have time to sit and edit every word I peck out.







It has been established many times and in many ways by many different investigators over a bout a 15 year period (none of this stuff is new...only new to folks who keep their vision narrow until something drifts into their field of view) that the mast cell density of diarrheic IBS victims increases over time.The focal point is at the outflow tract of the small bowel into the large bowel (ileocecal junction). It has also been shown to be higher lower down the colonic tract but the further you move from the ileocecal junction the lesser the difference.As we know mast cells primary function is immunoprotective...and it is also universal knowledge that mast cell density increases over time at a site of chronic immunochallenge....the nacent cells migrate to the site and settle in there where they are perceived to be needed through a complex mechanism you can learn about by reading any med school introductory immunology book.IgE specific to antigen is the principle mechanism of mast cell degranulation...and the principal immune dysfunction mechanism in classic allergic diseases: the body forms IgE specific to something it should not when first exposed and on subsequent exposure you get a 2-stage rapid onset hypersensitivity reaction (Type I Gel & Coombs reaction).Normally you should only "make IgE" to something actually dangerous...a pathogen. But allergic people can make it against inhalants or ingestants or both...and you can get cross reactivity.Anyway, this concentration of mast cells has been studied via colonoscopic biopsies and later laparoscopic biopsies for many years.This is combined in recent years (since 1994) with endoscopic and laparoscopic investigation of the UPPER bowel, since for years it has been obvious that the colon is not the primary shock organ in so called IBS subjects...at least not in those who have any episodic diarrhea (exaggerated evacuatory response).Now what has been seen by different people different ways and at different times in the small intestine starting at the jejunum. The upper bowel, this is the area where whatever you ingest is first examined during digestion by the immune system as to whether it is safe or not safe, a process which continues in the bloodstream, each with specific immune cells (mast cells and "GALT"-gut-associated-lymphatic-tissue in the mucosa; specific types of lymphocytes, macrophages and other types of immune cells in the blood stream and the things which regulate them...antibodies; major histocompatability complex; complement system ad nauseum).So when people look in the upper gut they have found mast cell activity, EC cell activity, and infiltration of specific lymphocytes, especially at the root ganglia of the gut nerves in that area...ouch...if any of these cells dump their stored or synthesized mediators you are going to get spasm, pain, altered motility, and all manner of things that people with so called IBS get...the type of inflammatory process now confirmed to exist in the d-linked IBS population.They have also found many times and in many ways that there are abnormal immune responses to staple foods which sometimes involve local IgE which cannot be detected in the circulation...they call this "intestinal allergy"...and you also can see provocation of the other cells by foods or additives as lymphocytic aggregates correspond to the presence of their internal mediators in the fluid recovered from the jejunum after some foods are introduced...and it varies from patient to patient.We also know that the stress-response is amplified by the release ogf these mediators locally and in the bloodstream, and that the reverse is true...that chronic stress will upregulate the immune response of both the mucosal system (mast cells GALT EC etc) as well as certain circulating immunocytes.So if one looks at the wide-array from an integrated perspective not a single perspective one sees that we have a circle phenomenon of both lost oral tolerance through altered immune response which is primary, and for certain altered stress response which is secondary.What is less certain, as is pointed out by such experts as Kevin Olden of the Mayo Clinic, is whether it is possible that in some patients chronic stress in one form or another is the primary event which then leads to upregulation of the immune response to staple foods as a secondary event.Most do not feel there is any evidence to suggest this is primary...rather that indeed the psychosocial problems of IBS patients elevate stress response but this is not causal of the condition rather consequential....the pathogensis lies elsewhere.Where is not yet clear...only WHAT is clear...what is weirdest is the presence of specific IgE to specific food antigens in the chyme in the upper gut, and the presence of mediators of cell-mediated reactions as well...but the IBS patients where this is a fact (diarrheic component) do not have circulating antibodies (IgE) to the provoking foods.So there is cadre of experts who are studying just this, just as there isa cadre studying just the window of the CNS and serotonergic pathways in symptoms generation.All bets remain open.What is sure is that, for example, the use of oral cromolyn sodium was experimented with extensively in IBS-d in both Italy and the U.K. It does result in stabilization of immunocyte responses, including mast cells as a primary target but not exclusive to mast cells...certain types of reactive circulating immunocytes become less reactive when CS is present.For awhile.Then you have to take more to get the same effect....symptoms start to return....so you take more....then more then more until you are pooping 80 capsules a dayFuggetaboudit.What you DO know is that once the pathogensis (whatever it is) if the 2/3 of IBS victims who suffer a d-component runs it s course and the symptoms become apparent, you can provoke the symptoms via food challenges which are different from one patient to another and that there are many classes of food sensitivities which provoke symptoms...from simple sensitivity to irritant chemical components, to specific immunologic reaction like pseudoallergy (lectins activating mast cells or histamine in foods for example), to local "intestinal" allergy (local IgE) to systemic cell mediated hypersensitivity (numerous mechanisms) to exaggerated response to normal stress events and stress related efferent stimuli, and/or to all of the above.So we know that we can reduce or eliminate symptoms with the proper patient-specific oligoantigenic diet, with CBT in some people, with HT in some people, and in "more people" with combinant therapy involving these modalities.But as yet there is still no integrated picture which can be applied to IBS as if it is an homogeneous disease entity...it seems more and more unlikely as evidence accumulates that this is the case. It looks more and more like COPD so to speak....several conditions which overlap and aggravate each other to varying degrees depending upon the patient.Also, no one knows yet if those mast cell density changes are permanent or temporary.but think of it this way...the mast cell population in any body tissue from skin to connective tissue to mucosa...wherever they are normally present...has sort of a "baseline normal population".Any stimuli, such as a local chronic provocation, will increase migration of cells to that site thus increase density.If the stimulus is permanent (like in some autoimmune diseases) the altered cell population remains as the stimulus remains...but remove the stimulus and you remove the need....over time the incredible adaptive abilities of the immune response then result in a return towards normal of the tissue counts...this applies not just to mast cells but any aggregation or accumulation of immunocytes at some site of insult.In the case of the subjects with mast cells loaded up in the cecum and no other infective process apparent....there is some chronic stimulus linked to the outflow from the small bowel most likely, as this is the seminal event, or stimulus, which causes this kind of localization....so if it is an IBS subject with the, called for now, "intestinal allergy problem"...if you can isolate and eliminate the antigen which is activating mast cells then you eliminate the stimulus and the cell counts should drop in time.This will also result of course in a reduction in the exaggerated stress response as well...these phenomena are integral...they are closely linked...they cannot be examined in a vaccum one from the other and any valid conclusions drawn only postulates based on observations of one subset of the entire equation or process.This is why it is so desirable to find someone who would do integrative research of each of the elements on the same patients at the same time. This is yet to occur...rather the "camps" defined by area of expertise, self-interest, or funding sources remain. So we have to find ways of at least making sure they are selecting their subjects the same way...Like all things-IBS there is NO nice tidy answer..though there are a lot of pieces parts here and thereï¿½many more than there were even just 3 years agoOh I wish I had time to go over to that IBS and MIGRAINE thread for awhile as there is a lot to talk about there to explain what we know about those comorbidities.Oh by the way...anyone with d-type IBS live in South Florida and want free oligoantigenic diet therapy in exchange for as much of your blood as you can bear to give?You will need to give blood, a number of times, and you will need to change your diet a and you will have to fill out some forms from time to time reporting your symptoms and assessing your Quality of Life....but you will also have a very high probability of feeling a lot better when you do.I gotta get time to go post that formally over on whatever board that as you post such stuff....we are developing an innovative QC system first of all and need a bunch of D-types and migraineurs! Donï¿½t have to be comorbid.But you have to be down here, sorry, for this work we are doingï¿½we need locals or at least ï¿½commutablesï¿½.Anyway until I do get it posted pass the word around we need a bunch of d-types or cyclics who live within driving distance of the West Palm to Miami corridor for some work specific to this subject.Sorry if Old MNL was again confusing like I used to be...it is still a subject which is innately confusing for everyone that is 100% objective and who takes an integrative view of the situation and the related literature. Hell read the clinical guidelines and standards most recently updated by AGA! Even AGA acknowledges there is no solid evidence-based data on IBS yet even now in spite of everythingï¿½.diagnostic, treatment standards and pathogenesis postulates all remain concensus-based. So what consensus you get depends on how you select the group by which you will form a consensus! So there is no consensus which is integrated!Anyway, if we donï¿½t operate from this perspective, if one is an adherent to a specific dogma, then it is very easy to answer any question or explain anything in simple terms because one need only massage the information to fit the dogma du jour, and there you have it! Simple answers.Just like it was for asthma, right up until the early 1960ï¿½s! yes ï¿½Asthma is a psychosomatic condition, related to stress response. Calm down. Have a smoke!ï¿½Oopsï¿½what? Whatï¿½s IgE? Inhaled antigen what?And so the Medical World Turns.














MNL


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## SpAsMaN* (May 11, 2002)

cromolyn sodium,anyone try this?In fact, what is it?


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## SpAsMaN* (May 11, 2002)

my mast cells are going nuts but what can i do?


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## ohnometo (Sep 20, 2001)

OMG







It's Mike...I am so glad that you stopped by for your input







Things is going ok here in WV except for the snow....I am still doing really good


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## eric (Jul 8, 1999)

yes well aware of other mast cells trigger, cold medications foods and even more, there are a lot.But a persons fight or flight goes off around 200 times a day. Probably even more in an IBSer.And yes foods can trigger them. But its very important that the act of eating in IBS triggers d, via another action in control of serotonin. which is known to be faulty in D predominate subjects. The act of eating does this, not a degranulated mast cell although that could contribute and that is one reason foods can trigger IBS, but foods can trigger IBS for other chemical reasons, such as stimulants for examaple, or gas for another. Readers' ExchangeDefining Stress in IBSFall 2003From Arizona -- Thank you so much for your efforts and support for those of us with GI disorders. Your first issue (Spring 2003) of Digestive Health Matters is both professional and informative. I would like to comment on one of the articles - "The CNS: Center for Neurovisceral Sciences and Women's Health at UCLA." I am encouraged to know that steps are being taken for funding research of IBS and interstitial cystitis. However, it is discouraging that researchers are still expending time and money to research "neurobiological mechanisms by which stress modulates brain-visceral interaction." I realize that stress is a popular theory in the discussion of IBS triggers, however, I believe this is completely backward and it is the chronic pain and totally unreliable bowel function of an IBS sufferer which causes the greatest stress. If research would focus on "fixing" the bowel, no doubt the panic and fear of IBS would be greatly alleviated.Comment from Emeran Mayer, M.D. -- In contrast to the common interpretation of the term "stress" as a psychological phenomenon, it should be understood as any real or perceived perturbation of an organism's homeostasis, or state of harmony or balance. For example, in this viewpoint a severe hemorrhage, starvation, extreme temperature, or worry about the unpredictable onset of abdominal pain all qualify as stressors -- some as "physical" stressors, others as "psychological" stressors. The fear to leave the house in the morning without knowing if one can make it to work without having to stop on the freeway because of an uncontrollable bowel movement, or the fear of experiencing uncontrollable abdominal discomfort during an important business meeting are sufficient stressors to activate the central stress system.The central stress system involves the release of chemical stress mediators in the brain (such as corticotropin releasing factor), which in turn orchestrate an integrated autonomic, behavioral, neuroendocrine, and pain modulatory response. This biological response in turn will alter the way the brain and the viscera interact, and this altered brain-gut interaction can result in worsening of IBS symptoms. Thus, pain and discomfort, fear of these symptoms, activation of the stress response, and modulation of the brain-gut interactions by stress mediators are part of a vicious cycle which need to be interrupted to produce symptom relief.The neurobiology of stress is not a theory, but a topic that can be studied in animal models, and one of the hottest topics in drug development for treatment of IBS (e.g., substance P antagonists, corticotropin releasing factor antagonists). http://www.aboutibs.org/Publications/StressDefined.html


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## eric (Jul 8, 1999)

yes well aware of other mast cells trigger, cold medications foods and even more, there are a lot.But a persons fight or flight goes off around 200 times a day. Probably even more in an IBSer.And yes foods can trigger them. But its very important that the act of eating in IBS triggers d, via another action in control of serotonin. which is known to be faulty in D predominate subjects. The act of eating does this, not a degranulated mast cell although that could contribute and that is one reason foods can trigger IBS, but foods can trigger IBS for other chemical reasons, such as stimulants for examaple, or gas for another. Readers' ExchangeDefining Stress in IBSFall 2003From Arizona -- Thank you so much for your efforts and support for those of us with GI disorders. Your first issue (Spring 2003) of Digestive Health Matters is both professional and informative. I would like to comment on one of the articles - "The CNS: Center for Neurovisceral Sciences and Women's Health at UCLA." I am encouraged to know that steps are being taken for funding research of IBS and interstitial cystitis. However, it is discouraging that researchers are still expending time and money to research "neurobiological mechanisms by which stress modulates brain-visceral interaction." I realize that stress is a popular theory in the discussion of IBS triggers, however, I believe this is completely backward and it is the chronic pain and totally unreliable bowel function of an IBS sufferer which causes the greatest stress. If research would focus on "fixing" the bowel, no doubt the panic and fear of IBS would be greatly alleviated.Comment from Emeran Mayer, M.D. -- In contrast to the common interpretation of the term "stress" as a psychological phenomenon, it should be understood as any real or perceived perturbation of an organism's homeostasis, or state of harmony or balance. For example, in this viewpoint a severe hemorrhage, starvation, extreme temperature, or worry about the unpredictable onset of abdominal pain all qualify as stressors -- some as "physical" stressors, others as "psychological" stressors. The fear to leave the house in the morning without knowing if one can make it to work without having to stop on the freeway because of an uncontrollable bowel movement, or the fear of experiencing uncontrollable abdominal discomfort during an important business meeting are sufficient stressors to activate the central stress system.The central stress system involves the release of chemical stress mediators in the brain (such as corticotropin releasing factor), which in turn orchestrate an integrated autonomic, behavioral, neuroendocrine, and pain modulatory response. This biological response in turn will alter the way the brain and the viscera interact, and this altered brain-gut interaction can result in worsening of IBS symptoms. Thus, pain and discomfort, fear of these symptoms, activation of the stress response, and modulation of the brain-gut interactions by stress mediators are part of a vicious cycle which need to be interrupted to produce symptom relief.The neurobiology of stress is not a theory, but a topic that can be studied in animal models, and one of the hottest topics in drug development for treatment of IBS (e.g., substance P antagonists, corticotropin releasing factor antagonists). http://www.aboutibs.org/Publications/StressDefined.html From - Report on the 5th International Symposium onFunctional Gastrointestinal Disorders"Preliminary work also suggests that there may be family interventions that help reduce the impact of functional GI disorders on children.3Shin Fukudo, Tohoku University School of Medicine, Japan discussed Possible Genetic Markers in Functional GI Disorders and Treatment Response, an emerging area of research. For some time it has been believed that brain-gut interactions -- autonomous activity in the GI tract and central nervous activity that influences bowel function in response to stressors -- play a major role in the origin and development (pathogenesis) of irritable bowel syndrome (IBS).Studies suggest that IBS patients have hyper-reactive bowels and unusually stress-sensitive brains. Studies by Dr. Fukudo's group include recent use of models to study serotonin (5-HT) reuptake transporter (SERT) genes, cross-cultural studies of 5-HT agents, and the effects of variations in the regions of the DNA strand that are the beginning of a gene (gene promoter regions) on one's responses to stress. Sensitization of the nerves (neurons) in the brain and the gut (intestines) may be due to a genetic effect as well as an acquired effect (resulting from a stimulus). More investigation on exploring genetic markers and therapeutic responses is warranted.4 http://www.iffgd.org/symposium2003factors.html Critical role of mast cells in inflammatory diseases and the effect of acute stress.Theoharides TC, Cochrane DE.Department of Pharmacology and Experimental Therapeutics, Tufts-New England Medical Center, Boston, MA, USAMast cells are not only necessary for allergic reactions, but recent findings indicate that they are also involved in a variety of neuroinflammatory diseases, especially those worsened by stress. In these cases, mast cells appear to be activated through their Fc receptors by immunoglobulins other than IgE, as well as by anaphylatoxins, neuropeptides and cytokines to secrete mediators selectively without overt degranulation. These facts can help us better understand a variety of sterile inflammatory conditions, such as multiple sclerosis (MS), migraines, inflammatory arthritis, atopic dermatitis, coronary inflammation, interstitial cystitis and irritable bowel syndrome, in which mast cells are activated without allergic degranulation.FYIHarvard healthThe Mind and the Immune Systemï¿½Part IOne of the standing mysteries of medicine is the relationship between the mind and physical healthï¿½how feelings, thoughts, attitudes, and behavior are related to physical illness, how psychological and social stress affect the likelihood of developing a disease or the ability to resist it, and how counseling for emotional problems can aid recovery from illness. One of the clues to this mystery lies in the immune system, the network that defends us against microbes and other invaders. Interest in the connections between the brain and the immune system has given birth to the discipline of psychoneuroimmunology.These systems communicate through the sympathetic nervous system and the endocrine glands, especially the hypothalamic-pituitary-adrenal (HPA) axis. Like the immune system, both are dedicated to the defense of the body against stress and danger, and both are directed from the same part of the brain, the hypothalamus. All threeï¿½the immune system, sympathetic nervous system, and HPA axisï¿½respond to some of the same transmitter chemicals.The sympathetic nervous system is part of the autonomic nervous system, which controls involuntary functions like heart rate, digestion, and breathing. The sympathetic nerves serve as an emergency response network, heightening the bodyï¿½s readiness to accept a challenge or escape in the face of danger. The sympathetic nerves are connected to various organs of the immune system, such as the thymus gland, the bone marrow, the spleen, and lymph nodes. Immune cells, including T cells, monocytes, and B cells, have receptors for the neurotransmitters released by sympathetic nerves. Damage to the hypothalamus and loss of sympathetic transmitters impairs the functioning of the immune system. An injection of antigens (foreign substances that activate the immune system) affects the concentration of sympathetic neurotransmitters in the brain.Immune LearningAnimal experiments show that the immune system can ï¿½learnï¿½ by association. In one experiment, rats drank sweetened water containing a drug that causes nausea and depresses the immune system. They became so sick that they avoided sweetened water for some time after the drug was removed. That behavioral conditioning eventually was extinguished (wore off), and they returned to drinking the waterï¿½only to start developing infections at an abnormally high rate. Apparently, by association with the immunosuppressant drug, sugared water was provoking a conditioned response that continued to suppress the ratsï¿½ immune systems even when it no longer affected their behavior.Another experiment involved mice bred to be genetically vulnerable to an autoimmune disease (one in which an overactive immune system attacks the bodyï¿½s own tissues). They were given a flavored solution containing a drug that suppresses the immune system, delaying the onset of the disease. Then most of the drug was removed, but as long as the flavor remained, the rats continued to drink the liquid and resist the disease. The immune system had learned by association to suppress itself when the animals recognized that taste.Conditioned learning can also enhance immune function, as another experiment showed. Mice were repeatedly forced to smell camphor while they were injected with a substance that stimulated the activity of natural killer (NK) cells, a type of white blood cell. When they were exposed to the smell of camphor without the injection, the activity of their NK cells still increased.Hormonal EffectsThe HPA axis regulates the bodyï¿½s activity through the circulation of the blood rather than directly through neural connections. The hypothalamus directs the pituitary gland to produce hormones that travel in the blood to the adrenal glands, where they cause the release of cortisol and other steroids as well as epinephrine (adrenaline) and its chemical relative norepinephrine (both of which also serve as neurotransmitters in the sympathetic system). These stress hormones influence the immune reaction through receptors on immune cells. Adrenaline, which prepares the body for immediate action, stimulates the immune system. One function of cortisol and related hormones (glucocorticoids) is to serve as a feedback mechanism that conserves energy by tuning down the emergency reaction when it is no longer needed. Rising cortisol levels signal the brain to shut down an immune response that threatens to become overactive.Thereï¿½s evidence that stress is associated with depressed immune function in one or another part of the system. In one study, the activity of NK cells declined in medical students preparing for an examination. Those who felt calmer and had a slower heart rate also showed fewer immune changes. In another study, unemployment slowed the multiplication of white blood cells in response to antigens. A survey found that unhappily married women had lower numbers of certain immune cells than women with happy marriages. Elderly people caring for relatives with Alzheimerï¿½s disease have higher than average levels of cortisol and low levels of antibody response to influenza vaccine. Stress delays the production of antibodies in mice infected with influenza virus and suppresses the activity of NK cells in animals inoculated with herpes simplex virus.Social stress can be even more damaging than physical stress. In a report published last year, some mice were put into a cage with a highly aggressive mouse two hours a day for six days. Other mice were kept in tiny cages without food and water for long periods. Both groups of mice were exposed to a bacterial toxin, and the socially stressed animals were twice as likely to die.Severe depression resembles a chronic stress response, and depressed patients often lack the normal daily variation in the production of cortisol. Depressed patients seem to have lower NK cell activity than healthy controls, possibly because of high cortisol levels. In one study, the lymphocytes (a type of white blood cell) of depressed and bereaved persons responded sluggishly to the substances that normally stimulate them to proliferate.Isolation can also suppress immune function. Infant monkeys separated from their mothers, especially if they are caged alone rather than in groups, generate fewer lymphocytes in response to antigens and fewer antibodies in response to viruses. Some studies have found lower NK cell activity in separated and divorced than in married men. NK cell activity also has been found to be lower in medical students who say they are lonely. In a year-long study of people caring for husbands or wives with Alzheimerï¿½s disease, changes in immune function were greatest in those who had the fewest friends and least outside help. In general, good social support is associated with better immune function in the elderly, even after correction for health habits, depression, anxiety, and life stress.The effect of traumatic stress on the immune system has been studied occasionally. According to one report, four months after the passage of Hurricane Andrew in Florida, people in the most heavily damaged neighborhoods showed red uced activity in four out of five immune functions. Similar results were found in a study of hospital employees after an earthquake in Los Angeles. And a report published last year suggested that men with a history of posttraumatic stress disorder (PTSD), even long after apparent recovery, had lower numbers of various immune cells and lower levels of immune activityï¿½possibly indicating a long-lasting suppression of the system. Another study found lower lymphocyte activity in abused women.But itï¿½s not easy to generalize about the effect of stress hormones and sympathetic nervous system activity on immune functioning. Much depends on the individual, the timing, the kind of stress, and the part of the immune system under consideration. The results of studies on depression, for example, are conflicting; it does not consistently suppress any part of the immune system except NK cells.Animal experiments suggest that the nervous system responds differently to acute and chronic stress. The acute stress reaction is often a healthy response to a challenge. But chronic stress may cause the feedback controls to fail, turning the emergency response into a condition that persists when it no longer has any use. Stress hormones and sympathetic activity remain at high levels, suppressing immune function and possibly promoting illness. The immune systems of people who are under chronic stress may also respond abnormally to acute stress.The Difference it MakesWhat matters most is whether the mindï¿½s influence on the immune system has the power to raise or lower the risk of illness or injury. On that issue only a little evidence is available.Healing of injuries. One study found that the wound from a biopsy healed more slowly in women under high emotional stress. In another experiment, a wound healed more slowly in students when it was inflicted before an examination rather than just before vacation. Slow healing has also been found in people caring for Alzheimerï¿½s patients.Colds and flu. Both observation and experiments suggest that stress makes people more susceptible to colds and other respiratory infections. In a one-year study, researchers asked 100 people to keep a diary recording their feelings and events in their lives. They were examined periodically for bacteria in throat cultures and virus antibodies in the blood. Stressful events were four times more likely to come before rather than after new infections. And people who developed a cold or other infection had often been feeling more angry and tense than usual.In an English study published in 1991, 420 people were given nose drops containing a cold virus after answering questions about their personality, health practices, and behavior. They were asked about feelings of frustration, nervousness, anxiety, and depression and about events such as loss of a job or deaths in the family. When the subjects were quarantined and monitored for nine days, those under greater stress were more likely to catch a cold.Researchers have continued to confirm this connection. In a study conducted in the late 1990s at the University of Pittsburgh, 276 healthy adults were given nose drops containing a cold virus. The symptoms were most severe in those who reported a high level of stress in their livesï¿½but only when it was prolonged stress caused by such problems as unemployment and troubled marriages. Resistance to the virus was correlated with strong social support, especially a variety of contacts with family, neighbors, friends, workmates, and fellow members of voluntary organizations. This effect was independent of smoking, alcohol consumption, and quality of sleep. People with the weakest (least diverse) social ties were four times more susceptible to colds than those with the strongest ties.Stress can also interfere with the response to a vaccine. In one study, flu shots were given to 32 people under high stress and 32 under low stress, matched for age, sex, and social class. The vaccine produced higher levels of antibodies in the low-stress group, and the high-stress people were more likely to become infected.The University of Pittsburgh researchers found a close association between difficulties in coping with stress, flu symptoms, and a specific immune response. Fifty-five volunteers were given nose drops containing a flu virus after answering questions about their ability to handle stress in their lives. The people with the most stress-related problems produced higher concentrations of interleukin-6, a chemical messenger that attracts immune cells to the site of an infection. They also produced more mucus (had stuffier noses) and generally developed more serious symptoms in direct proportion to the rise in their interleukin-6 levels. http://www.health.harvard.edu/hhp/article/content.do?id=537


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## eric (Jul 8, 1999)

"Revisiting IBS: Perspectives for the New Millennium--------------------------------------------------------------------------------Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder that affects millions of Americans. Care for patients with IBS often falls to the primary care physician. The pathophysiology of the disorder is still not entirely clear, and current treatment options are ineffective in many patients. At the 2000 American College of Gastroenterology's Annual Meeting, attendees convened for the presentations of three experts in the field, who outlined the latest research on the pathogenesis and treatment of this clinically challenging condition.This program was sponsored by the University of Kentucky through an unrestricted educational grant from Novartis Pharmaceuticals Corporation and Bristol-Myers Squibb Company.--------------------------------------------------------------------------------Brain Imaging: CNS Abnormalities in Patients with IBSThe lack of a clearcut pathophysiology and an often noted association between physical and psychological symptoms has led some clinicians to dismiss irritable bowel syndrome (IBS) as a condition that is "all in their head." However recent findings showing CNS abnormalities in patients with IBS may offer a new perspective on the etiology of this debilitating condition, characterized by abdominal discomfort and pain and altered bowel habits. Until recently, the presence and severity of IBS were measured only by gut function and the subjective perceptions of the patient. "Now, the use of functional brain imaging techniques is contributing to an increased under- standing of the pathophysiology of this disease and new target areas for treatment," said Emeran A. Mayer, MD, Professor of Medicine, Physiology, and Biobehavioral Sciences, and Director of the CURE Neuroenteric Disease Program at the University of California, Los Angeles.Pathophysiology of IBSIBS is a disease that develops as the result of an abnormally altered brain-gut interaction (Table 1). One manifestation of this alteration consists of aberrant output patterns of the emotional motor system, a part of the limbic system in the brain, in response to external (psychosocial) or internal (immune, nutrient) stressors. Outputs from the limbic system in the form of autonomic, pain modulatory, and neuroendocrine responses can be modu- lated by cognitive factors, such as the beliefs, thoughts, and emotions of the patient. Aberrant output of the emotional motor system in large part accounts for the constellation of symptoms that makes up IBS. "A hyperresponsiveness of circuits in the brain may be one common link to both the abnormal responses to internal inflammatory stressors and external psychosocial stressors," Dr. Mayer explained. Treatment is chosen with consideration of altered motility, visceral hypersensitivity, and the brain's role in modulating these factors.The autonomic regulatory systems affect not only muscle cells in the gut, but also other cell types, such as mast cells, enterochromaffin cells, and nerve cells of the enteric nervous system. Responses of some of these cells to autonomic modulation, for example in the form of tryptase secretion by mast cells or serotonin secretion by enterochromaffin cells, may play a role in the modulation of visceral afferent sensitivity. According to Dr. Mayer, such mechanisms may play a role in the development of stress-induced visceral hyperalgesia. Another form of visceral hypersensitivity may be related to altered arousal or hypervigilance toward visceral sensations. Such hypervigilance can result in decreased tolerance to balloon distension and lower discomfort thresholds. A cognitive factor involved in the development of hypervigilance is an increased threat appraisal of visceral sensations.Functional Brain Imaging TechniquesRecently, functional brain imaging techniques have been used to assess directly the activation of certain regions of the brain in response tovisceral stimulation. Today, these techniques, particularly functional magnetic resonance imaging, are being used to assess activation of brain circuits that process visceral afferent information from the gut.Dr. Mayer noted that there are distinct but overlapping brain circuits that relate to subjective perception of gut sensations, autonomic responses, and pain modulatory responses. Even in terms of subjective gut sensations, different overlapping circuits are present for intensity coding of the stimulus; threat appraisal of the stimulus; and attribution of primary affect, or "unpleasantness".Both serial and parallel pathways are involved in the processing of visceral sensory information and the control of descending modulatory systems. Input from the gut is derived from multiple channels, such as spinothalamic, vagal, and dorsal column pathways; different regions of the brain then code for intensity, appraise the threat of the stimulus, and determine the level of attention the brain attributes to the stimulus and the unpleasantness the patient experiences. These processes are modulated both by the stress- or arousal- activated system and by recollection of past experiences.Intensity Coding, Threat Appraisal, and UnpleasantnessIntensity coding. As visceral sensory information is delivered via the spinal cord, it is encoded for intensity in the anterior aspects of the insula, or visceral sensory cortex. PET scan studies of somatic and visceral experimental pain have shown that the insula most objectively and reliably encodes information. Interestingly, studies have also demonstrated a greater activation of the insula in male IBS patients, compared with female patients, when exposed to the same stimulus intensity.Threat appraisal and unpleasantness. The information that reaches the insula is "appraised" in the dorsal aspects of the anterior cingulate cortex. Blood flow changes in this part of the brain may also correlate with attentional processes and the subjective unpleasantness ratings in response to a somatic stimulus. The ventral (perigenual) cingulate cortex, which is rich in muopioid receptors, functions to encode the affective quality of the stimulus.In a study by Mayer and colleagues, rectal and sigmoid distension resulted in a lower activation of the ventral anterior cingulate cortex in patients with IBS compared with healthy controls, but an increased activation of the dorsal aspects of the anterior cingulate. Increased activation of an unspecified region of the anterior cingulate was also reported by Mertz and colleagues, in a functional MRI study.Modulatory factors. Finally, the CNS processing of sensory experience may be simultaneously modulated by two parallel pathways: memory-based modulation and stress- or arousal-induced modulation. The posterior parietal cortex, or sensory association cortex, forms a network with the hippocampus and the amygdala (the brain's memory centers) as well as with the lateral prefrontal cortex. Somatic pain studies have shown that, in response to a stimulus, the recall of a similar past event, along with subsequent interpretation of this memory in the lateral prefrontal cortex, plays a major role in the threat appraisal of a sensory experience. The second modulatory effect is the stress- or arousal-induced response. The pontine locus ceruleus is activated in response to potentially threatening experiences. This region then projects to nearly all other regions of the brain that receive visceral input, causing secretions of norepinephrine and arousal of these sections of the brain. When the secretion of norepinephrine is excessive, these target regions are inhibited. It is of interest that descending projections from the locus coeruleus complex to the sacral spinal cord appear to play a major role in the modulation of distal colonic motor and secretory function.ConclusionBrain imaging and other studies of IBS pathophysiology indicate that the perception of gut stimuli and altered autonomic responses to these stimuli are affected by activation of various parts of the brain, resulting in increased attention to these stimuli, greater unpleasantness of the subjective experience, greater threat appraisal, and greater arousal in response to visceral sensations. Further study may lead to new developments in treatment for persons with IBS.--------------------------------------------------------------------------------Table 1. Clinical Relevance of Altered Brain-Gut InteractionAltered attentional mechanismso Greater awareness of normally subliminal visceral afferent stimuliAltered affective stimulus processingo Greater unpleasantness of visceral sensations, including heartburn, bloating, fullness, abdominal pain, incomplete rectal evacuationAltered threat appraisalo Leads to fears such as not being close enough to a bathroom anything eaten may trigger abdominal painEnhanced arousalo Shared by clinical conditions frequently overlapping IBS, such as anxiety, panic disorder and PTSDo Arousal reduced by sedatives, anxiolytics, low-dose tricyclicso May respond to relaxation exercises"	posted 01-14-2004 12:32 AM "Revisiting IBS: Perspectives for the New Millennium--------------------------------------------------------------------------------Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder that affects millions of Americans. Care for patients with IBS often falls to the primary care physician. The pathophysiology of the disorder is still not entirely clear, and current treatment options are ineffective in many patients. At the 2000 American College of Gastroenterology's Annual Meeting, attendees convened for the presentations of three experts in the field, who outlined the latest research on the pathogenesis and treatment of this clinically challenging condition.This program was sponsored by the University of Kentucky through an unrestricted educational grant from Novartis Pharmaceuticals Corporation and Bristol-Myers Squibb Company.--------------------------------------------------------------------------------Brain Imaging: CNS Abnormalities in Patients with IBSThe lack of a clearcut pathophysiology and an often noted association between physical and psychological symptoms has led some clinicians to dismiss irritable bowel syndrome (IBS) as a condition that is "all in their head." However recent findings showing CNS abnormalities in patients with IBS may offer a new perspective on the etiology of this debilitating condition, characterized by abdominal discomfort and pain and altered bowel habits. Until recently, the presence and severity of IBS were measured only by gut function and the subjective perceptions of the patient. "Now, the use of functional brain imaging techniques is contributing to an increased under- standing of the pathophysiology of this disease and new target areas for treatment," said Emeran A. Mayer, MD, Professor of Medicine, Physiology, and Biobehavioral Sciences, and Director of the CURE Neuroenteric Disease Program at the University of California, Los Angeles.Pathophysiology of IBSIBS is a disease that develops as the result of an abnormally altered brain-gut interaction (Table 1). One manifestation of this alteration consists of aberrant output patterns of the emotional motor system, a part of the limbic system in the brain, in response to external (psychosocial) or internal (immune, nutrient) stressors. Outputs from the limbic system in the form of autonomic, pain modulatory, and neuroendocrine responses can be modu- lated by cognitive factors, such as the beliefs, thoughts, and emotions of the patient. Aberrant output of the emotional motor system in large part accounts for the constellation of symptoms that makes up IBS. "A hyperresponsiveness of circuits in the brain may be one common link to both the abnormal responses to internal inflammatory stressors and external psychosocial stressors," Dr. Mayer explained. Treatment is chosen with consideration of altered motility, visceral hypersensitivity, and the brain's role in modulating these factors.The autonomic regulatory systems affect not only muscle cells in the gut, but also other cell types, such as mast cells, enterochromaffin cells, and nerve cells of the enteric nervous system. Responses of some of these cells to autonomic modulation, for example in the form of tryptase secretion by mast cells or serotonin secretion by enterochromaffin cells, may play a role in the modulation of visceral afferent sensitivity. According to Dr. Mayer, such mechanisms may play a role in the development of stress-induced visceral hyperalgesia. Another form of visceral hypersensitivity may be related to altered arousal or hypervigilance toward visceral sensations. Such hypervigilance can result in decreased tolerance to balloon distension and lower discomfort thresholds. A cognitive factor involved in the development of hypervigilance is an increased threat appraisal of visceral sensations.Functional Brain Imaging TechniquesRecently, functional brain imaging techniques have been used to assess directly the activation of certain regions of the brain in response tovisceral stimulation. Today, these techniques, particularly functional magnetic resonance imaging, are being used to assess activation of brain circuits that process visceral afferent information from the gut.Dr. Mayer noted that there are distinct but overlapping brain circuits that relate to subjective perception of gut sensations, autonomic responses, and pain modulatory responses. Even in terms of subjective gut sensations, different overlapping circuits are present for intensity coding of the stimulus; threat appraisal of the stimulus; and attribution of primary affect, or "unpleasantness".Both serial and parallel pathways are involved in the processing of visceral sensory information and the control of descending modulatory systems. Input from the gut is derived from multiple channels, such as spinothalamic, vagal, and dorsal column pathways; different regions of the brain then code for intensity, appraise the threat of the stimulus, and determine the level of attention the brain attributes to the stimulus and the unpleasantness the patient experiences. These processes are modulated both by the stress- or arousal- activated system and by recollection of past experiences.Intensity Coding, Threat Appraisal, and UnpleasantnessIntensity coding. As visceral sensory information is delivered via the spinal cord, it is encoded for intensity in the anterior aspects of the insula, or visceral sensory cortex. PET scan studies of somatic and visceral experimental pain have shown that the insula most objectively and reliably encodes information. Interestingly, studies have also demonstrated a greater activation of the insula in male IBS patients, compared with female patients, when exposed to the same stimulus intensity.Threat appraisal and unpleasantness. The information that reaches the insula is "appraised" in the dorsal aspects of the anterior cingulate cortex. Blood flow changes in this part of the brain may also correlate with attentional processes and the subjective unpleasantness ratings in response to a somatic stimulus. The ventral (perigenual) cingulate cortex, which is rich in muopioid receptors, functions to encode the affective quality of the stimulus.In a study by Mayer and colleagues, rectal and sigmoid distension resulted in a lower activation of the ventral anterior cingulate cortex in patients with IBS compared with healthy controls, but an increased activation of the dorsal aspects of the anterior cingulate. Increased activation of an unspecified region of the anterior cingulate was also reported by Mertz and colleagues, in a functional MRI study.Modulatory factors. Finally, the CNS processing of sensory experience may be simultaneously modulated by two parallel pathways: memory-based modulation and stress- or arousal-induced modulation. The posterior parietal cortex, or sensory association cortex, forms a network with the hippocampus and the amygdala (the brain's memory centers) as well as with the lateral prefrontal cortex. Somatic pain studies have shown that, in response to a stimulus, the recall of a similar past event, along with subsequent interpretation of this memory in the lateral prefrontal cortex, plays a major role in the threat appraisal of a sensory experience. The second modulatory effect is the stress- or arousal-induced response. The pontine locus ceruleus is activated in response to potentially threatening experiences. This region then projects to nearly all other regions of the brain that receive visceral input, causing secretions of norepinephrine and arousal of these sections of the brain. When the secretion of norepinephrine is excessive, these target regions are inhibited. It is of interest that descending projections from the locus coeruleus complex to the sacral spinal cord appear to play a major role in the modulation of distal colonic motor and secretory function.ConclusionBrain imaging and other studies of IBS pathophysiology indicate that the perception of gut stimuli and altered autonomic responses to these stimuli are affected by activation of various parts of the brain, resulting in increased attention to these stimuli, greater unpleasantness of the subjective experience, greater threat appraisal, and greater arousal in response to visceral sensations. Further study may lead to new developments in treatment for persons with IBS.--------------------------------------------------------------------------------Table 1. Clinical Relevance of Altered Brain-Gut InteractionAltered attentional mechanismso Greater awareness of normally subliminal visceral afferent stimuliAltered affective stimulus processingo Greater unpleasantness of visceral sensations, including heartburn, bloating, fullness, abdominal pain, incomplete rectal evacuationAltered threat appraisalo Leads to fears such as not being close enough to a bathroom anything eaten may trigger abdominal painEnhanced arousalo Shared by clinical conditions frequently overlapping IBS, such as anxiety, panic disorder and PTSDo Arousal reduced by sedatives, anxiolytics, low-dose tricyclicso May respond to relaxation exercises" http://cp.yahoo.net/search/cache?p=ibs+sym.../pcp2000_01.htm Recent Advances in Pathophysiology of Irritable Bowel SyndromeDepartment of Behavioral Medicine, Tohoku University Graduate School of MedicineShin Fukudo, M.D., PhD.The gastrointestinal tract has autonomous activity and responds to the luminal stimuli moment-to-moment. Since theWalter B. Cannon's era, it also has been known that central nervous activity influences on the bowel function. Recentadvances in research clearly demonstrate mutual and reciprocal interactions between these two organs. These phenomena,the brain-gut interactions, are believed to play a major role in pathogenesis of functional gastrointestinal disorders.Irritable bowel syndrome (IBS) is a prototype of functional gastrointestinal disorders. The brain-to-gut effects and thegut-to-brain effects are supposed to form complex circuits.Psychosocial stress is known to exacerbate IBS symptoms. Drossman et al. reported that stress affected bowelfunction in 84 % of IBS subjects or induced abdominal pain in 69% of them. Whitehead et al. confirmed that IBSsubjects showed steeper slope of regression line relating stress to bowel symptoms, suggesting they have a greaterreactivity to stress. To see the effect of of mental stress on the bowel motility, we loaded mirror tracing stress to theIBS patients. The IBS patients showed higher colonic motility index during and after stress than the controls. Welganet al. reported anger increased frequency of myoelectrical activity and motility of the colon in the IBS patients. Thesetwo independent data express the stress-induced pathophysiology of colonic motility in the IBS patients.Simultaneous manometric measurements in the duodenum during and after the mental arithmetic stress expressed lessphase I, period of quiescence, and phase III, period of powerful rhythmic contractions with 11-12 cycle per min, ofmigrating motor complex in the IBS patients. Phase II, period of contractions with irregular intervals, prolonged moreprominently in the IBS patients. Twenty-four hrs prolonged recording in duodenal motility in the IBS patients disclosedexistence of dysmotility patterns during phase II. They were burst activity and clustered contractions. Arousal of thebrain has great impact on duodenal motility. In most individuals, either in the IBS patients or the controls, phase II isdominant during the awake, while it attenuates during the sleep.Dysmotility patterns more than 15 min of duration were limited in the IBS patients during the awake, suggestingprogrammed function of the enteric nervous system is disturbed by perturbations from the brain. Motility patterns of thesmall bowel during sleep were normal in the IBS patients.Power spectral analyses of electroencephalogram (EEG) demonstrated that stress decreased a-power and increasedb-power in the IBS patients and the controls. However, in the IBS patients, these changes were enhanced. Thesefindings implies that the IBS patients may have sensitive brain to stress. Moreover, abnormal sleep patterns of rapid eyemovement (REM) in the IBS patients are also reported by Kumar et al.- 113 ---------------------------------------------------------------------------------Page 2??????? ?????? 2002From these observations, the IBS patients are suggested to have stress-sensitive brain and hyper-reactive bowel. Manyneurotransmitters are supposed to be involved in these mechanisms. Corticotropin-releasing hormone (CRH) is one ofthe most plausible candidates to play a crucial role in pathogenesis of IBS. CRH is a 41-amino acids-peptide producedmainly in the hypothalamus and distributed in the colon. Stress releases hypothalamic CRH, resulting pituitary secretionof adrenocorticotropic hormone (ACTH). In rodents, CRH antagonists inhibits stress-induced alterations in the colonicmotility. Exogenous administration of CRH, intracerebroventricularly or intravenously, accelerates colonic transit. CRHmildly provokes colonic motility in humans. While in the IBS patients, CRH stimulates colonic motility moreprominently. ACTH secretion to CRH in the IBS patients is also exaggerated.Recently, studies on gut-to-brain direction are more focused on the research. That is because progressive knowledgedemonstrates that the brain plays a major role in the integration of the signal derived from the peripheral organs. Thesestudies are performed mainly using the barostat technique. Visceral hyperalgesia in the IBS patients are first reported byRichie and his group, replicated by Whitehead, and further investigated by Mayer et al. Repetitive mechanicalstimulation of the sigmoid colon provoked increase in colonic motility in the descending colon of the IBS patients,suggesting visceral hyperalgesia and simultaneous abnormal intramural reflex. Cerebral evoked potentials, as shown inthe first negative1-positive1-negative2-triphasic waves, were obtained using EEG recordings during the gut stimulation.IBS patients have abnormal patterns of viscerosensory evoked potentials. IBS patients were reported to have abnormalactivation patterns of the regional cerebral blood flow in response to the mechanical distention of the rectum.In this context, the IBS patients have stress-sensitive brain, hyper-reactive bowel motility, and visceral hyperalgesia toa larger or lesser extent. The initial involved point may be either. This notion is also supported by the report fromRead's group in the Lancet. When acute enterocolitis hits the bowel, patients with high scores for anxiety, depression,somatization, and neurotic trait become IBS. Once the vicious cycle is formed, visceral hyperalgesia will changeintramural reflex as well as brain neurotransmitter release, resulting exaggerated stress-sensitivity. Therapeutic approachfor IBS should be performed along these knowledge. Further investigations on reciprocal brain-gut interaction in IBS iswarranted.- 114 - http://cp.yahoo.net/search/cache?p=+hyper+...ng/07806192.pdf Altered Visceral Perception Modulation Confirmed In Irritable Bowel PatientsA DGReview of :"Irritable bowel syndrome patients show enhanced modulation of visceral perception by auditory stress."American Journal of Gastroenterology01/29/2003By Elda HauschildtPatients with irritable bowel syndrome (IBS) have altered stress-induced modulation of visceral perception, confirms research from the United States.Investigators, from the University of California at Los Angeles, found that IBS patients rate visceral stimulus during stress significantly higher in terms of intensity and unpleasantness than do healthy controls."IBS patients also reported higher ratings of stress, anger and anxiety during the stress compared with the relaxing condition, whereas controls had smaller and non-significant subjective responses," they explain.Symptoms from IBS are known to be sensitive to psychological stressors. This could occur because of enhanced responsiveness of the emotional motor system, a network of brain circuits modulating arousal, viscerosomatic perception and autonomic responses associated with emotional response, the researchers point out.Rectal balloon distension during experimentally induced psychological stress was used to test psychological reactions in 15 IBS patients and 14 healthy controls to assess whether IBS patients demonstrate altered perceptual response.The mild stress condition involved dichotomous listening to two conflicting types of music. The control condition also involved listening but to relaxing nature sounds. Stress and relation stimuli were delivered over a 10-minute listening period preceding and during rectal distensions.Intensity and unpleasantness ratings measured included visceral sensation, subjective emotional response and heart rate. Neuro-endocrine measures were also taken.The investigators found that unlike healthy controls, IBS patients gave significantly higher ratings of the visceral stimulus in terms of intensity and unpleasantness.American Journal of Gastroenterology, 2003; 98: 135-143. "Irritable bowel syndrome patients show enhanced modulation of visceral perception by auditory stress." http://www.docguide.com/news/content.nsf/n...52568880078C249 Stress and the GutDr. Howard MertzAssociate Professor of Medicine and RadiologyVanderbilt UniversityStress is a ubiquitous condition that affects all people. Stress can be mental or physical, although in the context of this article the focus will be mental stress. Mental stress involves challenge, threat or worry about future adverse events. Such stress activates the brainï¿½s stress response systems, which in turn effect the body. Many of the bodyï¿½s major systems are altered by stress (cardiovascular, muscular, urinary, gastrointestinal, sweat glands, etc) often with adverse consequences. Gastrointestinal function is particularly influenced by stress. Common gastrointestinal symptoms due to stress are heartburn, indigestion, nausea and vomiting, diarrhea, constipation and associated lower abdominal pain. These symptoms and the alterations in intestinal function that cause them are becoming understood.Gastrointestinal Stress Reactions in Animals and CRFIn animals such as rats, stress can be induced in experimental situations. When rats are wrap restrained, or placed on a small platform surrounded by water they become stressed. During these situations, alterations in motility of the gut occur. The upper gut, including the stomach and small intestine, exhibits markedly reduced transit. This may be a defense mechanism to promote vomiting and reduce oral intake. Conversely the large bowel motility increases with increased stool output and transit speed. This may be a defense mechanism to eliminate toxins. We have learned that a hormone called corticotropin releasing factor (CRF) influences these changes. CRF is released from nerve cells in the hypothalamus of the brain. These nerve cells release the hormone via long processes into other parts of the brain such as the locus ceruleus, where arousal and autonomic nervous system changes are mediated. In rats, injection of CRF blockers into the brain fluid diminishes the stress induced motility changes in the gut. CRF directly injected into the brain fluid mimics the stress response closely (Figure 1). CRF also stimulates the gut directly via CRF-1 and CRF-2 receptors. CRF-1 receptors stimulate colonic contractions, while CRF-2 receptors reduce upper gut activity. Antagonists to CRF-1 receptors are currently being tested for treatment of depression, and may become available for testing in functional bowel disorders as well.Brain Areas Involved in Stress ReactionTwo of the primary brain regions involved in stress reactivity are the hypothalamus and the locus ceruleus. Activation of the hypothalamus by stress is likely to be mediated in part by the limbic brain (particularly the amygdala and hippocampus) and partly by the locus ceruleus in the brainstem. The locus ceruleus and the hypothalamus actually stimulate each other, creating the potential for a vicious cycle, where a stress reaction in one region stimulates the other, which in turn stimulates the first to react even more. The limbic system is a group of connected and related brain regions that mediate emotions and flight or fight attitudes. The limbic or ï¿½emotional brainï¿½ is more primitive by evolutionary standards, and is not necessarily under control by the higher intellectual cortex. This system receives sensory and higher cortical inputs, calls upon memories and determines the threat level imposed by a stimulus. The amygdala for instance is a limbic structure in the base of the brain that is important in anger and rage. In cats, electrical stimulation of the amygdala causes hissing, back arching and the hair to stand on end, typical of anger and defense postures in cats. In animals that have damage to the amygdala a placid state results in which anger cannot be induced. Inputs to the amygdala are thought to originate from the hippocampus, the cingulate cortex and other parts of the limbic sytem. The locus ceruleus is located in the pontine portion of the brainstem. The locus ceruleus is the source of most of the stimulant neurotransmitter norepinephrine in the nervous system. Cells here project to other brain areas, releasing norepinephrine to activate other systems and increase arousal and alertness. Release of norepinephrine increases heart rate, blood pressure and primes the muscles and nervous system for fight or flight. This reaction is not helpful in routine stress of daily activities. If the stress reaction is excessive or the perceived threat too frequent, tachycardia (racing heart), hypertension, muscle tension, bowel spasms and dyspepsia can result.Hypothalamic-Pituitary-Adrenal AxisCRF release is the first step in activation of the hypothalamic-pituitary-adrenal axis (HPA axis) involved in stress response. This is the major endocrine (hormonal) response system to stress. Release of CRF by the hypothalamus stimulates the pituitary gland immediately underneath it. The pituitary gland responds to CRF by release of adreno-corticotropic hormone (ACTH) to stimulate adrenal gland secretion of the stress hormone cortisol. Cortisol promotes fluid and salt retention and impairs inflammation, functions helpful in the short term during flight or fight situations or injury. Again, if the HPA system is activated too frequently adverse health outcomes such as hypertension (from salt retention) and impaired immune function (from excess cortisol) may result. The CRF system and the norepinephrine systems work together to respond to stress with resultant changes in bodily functions that prepare for flight or fight. (Figure 2)Gastrointestinal Stress Response in HumansHumans respond to stress in similar ways to animals. A variety of human studies indicate stress promotes decreased gastric emptying and accelerated colonic transit in normal volunteers. A pioneering study by Almy measured colonic contractions during flexible sigmoidoscopy. The volunteers were told that a cancer was found, leading to abrupt increases in colonic contractions, which resolved after the hoax was explained. Other stressors such as ball-sorting, driving in city traffic and mentally challenging listening tasks similarly increase colonic contractions and reduce gastric motility. Recent data also indicates that intestinal sensitivity increases with stress compared to relaxation. This effect may lower the threshold for sensing intestinal events. In gastroesophageal reflux for example, psychological stressors can increase heartburn symptoms. Analysis of the esophageal pH (measurement of acid) indicates that the amount of reflux doesnï¿½t increase during stress, but the probability of feeling a reflux as heartburn does increase. In one small study of normal controls, intravenous infusion of CRF induced greater rectal sensitivity to balloon distension. It may be that the sensitizing effects of stress on the gut are partly mediated by the stress hormone CRF.Irritable Bowel Syndrome and Functional DyspepsiaTwo of the major causes of uncomfortable or painful intestinal symptoms are irritable bowel syndrome (IBS) and functional dyspepsia. IBS occurs in approximately 12% of people world-wide. Dyspepsia (indigestion/upper abdominal discomfort) is also very common. The majority of dyspepsia is functional, that is not associated with ulcers, gallstones, reflux esophagitis or cancer. In both of these common disorders, motility and sensory changes are present which mimic the stress state. Both disorders demonstrate hypersensitivity of the gut (either stomach or intestine). Both disorders demonstrate alterations in motor function of the gut typical of stress and CRF-induced changes. In functional dyspepsia the stomach generally has mildly reduced emptying and reduced accommodation of meals. In IBS, colonic contractions are generally increased. Furthermore, IBS subjects appear to have increased stress responsiveness in the gut. In one study, IBS patients and healthy controls both underwent ambulatory motility recordings in the colon. Both groups were confronted on return to the lab (ï¿½youï¿½re lateï¿½, ï¿½you came to the wrong windowï¿½, ï¿½now the study may need to be repeatedï¿½). Colonic motility jumped up in the IBS patients during confrontation, but not in healthy volunteers.(Figure 3) IBS patients may also have greater sensitivity to the stress hormone CRF. Infusion of CRF intravenously to IBS patients and controls in one study caused significantly greater colonic motor responses in IBS patients. Another study indicates that listening stress increases rectal sensitivity to balloon distension in IBS patients but not controls. It appears both intestinal motility and sensory responses to stress are heightened in IBS patients. These alterations are likely to cause symptoms such as diarrhea and intestinal cramps due to increased contractions of the gut and increased sensitivity of the gut during stress. The chemical mediators of these changes are not yet established, although alterations in CRF release or CRF receptors may be implicated to some extent in functional bowel diseases.IBS (and other functional bowel symptoms) are generally worsened by stress. In fact recent research has indicated that IBS symptoms tend to resolve in those without major psychosocial stressors. Conversely, symptoms are persistent in subjects with ongoing ï¿½threateningï¿½ psychosocial stressors. The onset of IBS and functional dyspepsia often begin with bereavement, abuse or other major negative life events. Emotional distress is very common in IBS patients, particularly those who seek medical treatment for the condition. Anxiety and depression are significantly increased in IBS patient populations, present in nearly 40%. Psychosocial distress appears much less common in IBS sufferers who do not seek medical care. Population based surveys, however, do still suggest tendencies toward emotional reactivity in people with IBS. Accordingly, stress modification, psychotherapy and hypnosis appear helpful for IBS and functional dyspeptic symptoms. Tricyclic antidepressants also appear effective for IBS and other functional bowel symptoms, even in low doses. Recent evidence indicates the drugs may work by reducing the brainï¿½s response to intestinal pain during stress. Sedatives such as the benzodiazepine Librium can reduce the effect of stress on the gut. During ball sorting challenge, Librium blunts the colonic motor response to mental stress in IBS patients. This effect may explain the benefits of combined sedative-anti-spasmodic drugs for IBS.SummaryThere is much yet to learn about the effects of stress on the gastrointestinal tract. The exact neural and hormonal pathways that mediate excess gut sensitivity and altered contractility during stress are not defined. Where these pathways are excessive or dysfunctional in IBS, functional dyspepsia and other GI disorders is unclear. Specific neurotransmitters are likely to underlie the gastrointestinal stress reaction, and may be amenable to pharmacologic blockade. Psychological therapies are likely to blunt the stress response as well. New tools such as brain imaging to study brain responses to stressors and drugs, and molecular biology to study function of neurotransmitters and their receptors are likely to lead to better understanding of the stress response and its role in disease states. Based on this knowledge, advances in pharmacology may lead to better drug therapies to address these important health problems.www.med.unc.edu/wrkunits/...elcome.htmFYIFrom Medscape GastroenterologyMEDLINE Abstracts: Serotonin Signaling and Visceral Hypersensitivity in IBSPosted 10/23/2003What's new concerning the role of serotonin signaling and mechanisms of visceral hypersensitivity in the pathophysiology of irritable bowel syndrome (IBS)? Find out in this easy-to-navigate collection of recent MEDLINE abstracts compiled by the editors at Medscape Gastroenterology.--------------------------------------------------------------------------------Serotonin and Its Implication for the Management of Irritable Bowel SyndromeGershon MDRev Gastroenterol Disord. 2003;3(suppl 2):S25-S34Our understanding of the enteric nervous system (ENS) has evolved from the "classical" view, in which the brain controls all enteric behavior, to the current view, which holds that enteric innervation is one of local control within the bowel, modified by a bidirectional "dialogue" with the brain. The ENS independently controls enteric reflexes through intrinsic primary afferent neurons, which monitor intraluminal conditions. This monitoring is accomplished through the use of enteroendocrine cells in the mucosa, the best known of which are the serotonin-containing enterochromaffin cells. This article describes the roles that serotonin, specific serotonin-receptor subtypes, and the serotonin reuptake transporter play in the ENS and in the communication between the ENS and central nervous system. The way in which these findings have implicated serotonin in irritable bowel syndrome is discussed.Systematic Review: Serotonergic Modulators in the Treatment of Irritable Bowel Syndrome--Influence on Psychiatric and Gastrointestinal SymptomsKilkens TO, Honig A, Rozendaal N, Van Nieuwenhoven MA, Brummer RJAliment Pharmacol Ther. 2003 ;17:43-51Background: Both central and peripheral serotonergic modulators are used in the treatment of irritable bowel syndrome. The majority of patients with irritable bowel syndrome presenting to a gastroenterologist demonstrate affective dysregulation. Serotonin may play a regulatory role in both gastrointestinal motility and sensitivity, as well as in affective dysregulation, in irritable bowel syndrome.Aim: To analyse, systematically, randomized controlled trials studying the influence of serotonergic modulators on both gastrointestinal and psychiatric symptoms in irritable bowel syndrome, in order to elucidate baseline irritable bowel syndrome symptomatology and possible differential effects of serotonergic modulation on this symptomatology.Methods: A standardized qualitative analysis was performed of studies investigating the influence of serotonergic modulators on both gastrointestinal and psychiatric symptoms in irritable bowel syndrome using a blind review approach. The studies were ranked according to their total quality score (maximum 100 points).Results: Eleven studies fulfilled the entry criteria, six of which scored above 55 points. An association between gastroenterological and psychiatric changes was present in five of the six studies.Conclusions: The results strengthen the serotonergic association between gastroenterological and psychiatric symptoms. Adjusted guidelines for combined gastrointestinal and psychiatric assessments are recommended in order to further elucidate the serotonergic interaction between gastrointestinal and psychiatric symptoms.Tegaserod and Other Serotonergic Agents: What Is the Evidence?Chey WDRev Gastroenterol Disord. 2003;3(suppl 2):S35-S40Through effects on gastrointestinal motor and secretory function as well as visceral sensation, serotonin (5-HT) plays a key role in the pathogenesis of irritable bowel syndrome (IBS). In particular, 5-HT3 and 5-HT4 receptors appear to be very important in IBS. This article critically appraises the evidence supporting the use of the 5-HT3 receptor antagonist alosetron in the treatment of women with diarrhea-predominant IBS. The safety profile and restricted-use program for alosetron is also reviewed. This discussion is followed by a comprehensive review of the efficacy and safety data in support of tegaserod for women with constipation-predominant IBS.Sex Differences of Brain Serotonin Synthesis in Patients With Irritable Bowel Syndrome Using Alpha-11C Methyl-L-Tryptophan, Positron Emission Tomography and Statistical Parametric MappingNakai A, Kumakura Y, Boivin M, et alCan J Gastroenterol. 2003;17:191-196Background: Irritable bowel syndrome (IBS) is the most common functional bowel disorder and has a strong predominance in women. Recent data suggest that the brain may play an important role in the pathophysiology of IBS in the brain-gut axis. It is strongly suspected that serotonin (5-HT), a neurotransmitter found in the brain and gut, may be related to the pathophysiology of IBS. It is reported that a 5-HT3 antagonist is effective only in female patients with diarrhea-predominant IBS.Objective: In the present study, 5-HT synthesis was measured using positron emission tomography, with alpha-11 Cmethyl-L-tryptophan as the tracer, in patients with IBS. The aim of the present study was to compare 5-HT synthesis in the IBS patients with that in the controls, and to compare 5-HT synthesis between male and female IBS patients.Methods: Six male and six female nonconstipated IBS patients were scanned. Age-matched healthy volunteers were scanned as controls. Eighty minute dynamic scans were performed. Functional 5-HT synthesis images were analyzed using statistical parametric mapping.Results: 5-HT synthesis was greater only in the female IBS patients in the right medial temporal gyrus (multimodal sensory association cortex) compared with the female controls (P 0.001).Conclusions: The greater brain 5-HT synthesis in the female IBS patients than in the controls may be related to the pathological visceral pain processing of the IBS patients, a larger female predominance of the disorder, and the sex difference of the efficacy of the 5-HT3 antagonist in treatment.Sex-Related Differences in IBS Patients: Central Processing of Visceral StimuliNaliboff BD, Berman S, Chang L, et alGastroenterology. 2003;124:1738-1747Background & Aims: Women have a higher prevalence of irritable bowel syndrome (IBS) and possible differences in response to treatment, suggesting sex-related differences in underlying pathophysiology. The aim of this study was to determine possible sex-related differences in brain responses to a visceral and a psychological stressor in IBS.Methods: Regional cerebral blood flow measurements using H(2)(15)O positron emission tomography were compared across 23 female and 19 male nonconstipated patients with IBS during a visceral stimulus (moderate rectal inflation) and a psychological stimulus (anticipation of a visceral stimulus).Results: In response to the visceral stimulus, women showed greater activation in the ventromedial prefrontal cortex, right anterior cingulate cortex, and left amygdala, whereas men showed greater activation of the right dorsolateral prefrontal cortex, insula, and dorsal pons/periaqueductal gray. Similar differences were observed during the anticipation condition. Men also reported higher arousal and lower fatigue.Conclusions: Male and female patients with IBS differ in activation of brain networks concerned with cognitive, autonomic, and antinociceptive responses to delivered and anticipated aversive visceral stimuli.Functional Brain Imaging in Irritable Bowel Syndrome With Rectal Balloon-Distention by Using fMRIYuan YZ, Tao RJ, Xu B, et alWorld J Gastroenterol. 2003;9:1356-1360Aim: Irritable bowel syndrome (IBS) is characterized by abdominal pain and changes in stool habits. Visceral hypersensitivity is a key factor in the pathophysiology of IBS. The aim of this study was to examine the effect of rectal balloon-distention stimulus by blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) in visceral pain center and to compare the distribution, extent, and intensity of activated areas between IBS patients and normal controls.Methods: Twenty-six patients with IBS and eleven normal controls were tested for rectal sensation, and the subjective pain intensity at 90 ml and 120 ml rectal balloon-distention was reported by using Visual Analogue Scale. Then, BOLD-fMRI was performed at 30 ml, 60 ml, 90 ml, and 120 ml rectal balloon-distention in all subjects.Results: Rectal distention stimulation increased the activity of anterior cingulate cortex (35/37), insular cortex (37/37), prefrontal cortex (37/37), and thalamus (35/37) in most cases. At 120 ml of rectal balloon-distention, the activation area and percentage change in MR signal intensity of the regions of interest (ROI) at IC, PFC, and THAL were significantly greater in patients with IBS than that in controls. Score of pain sensation at 90 ml and 120 ml rectal balloon-distention was significantly higher in patients with IBS than that in controls.Conclusion: Using fMRI, some patients with IBS can be detected having visceral hypersensitivity in response to painful rectal balloon-distention. fMRI is an objective brain imaging technique to measure the change in regional cerebral activation more precisely. In this study, IC and PFC of the IBS patients were the major loci of the CNS processing of visceral perception.Role of Visceral Sensitivity in the Pathophysiology of Irritable Bowel SyndromeDelvaux MGut. 2002;51(suppl 1):i67-i71Visceral hypersensitivity has been recognised as a characteristic of patients with irritable bowel syndrome (IBS). It may be involved in the pathogenesis of abdominal pain/discomfor


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## floridian2 (Dec 1, 2003)

Mast cell degranulation/histamine release is inhibited by magnolia bark, which also inhibits IgE activity and inflammitory leukotrienes.Magnolia bark also reduces anxiety. The anxiolytic effect is comparable to diazepam (valium), but it takes a few days to kick in. The anti-anxiety action is non-sedating, and longer acting than valium. Magnolia appears in several Chinese formulas for constipation, but this is usually with other laxative herbs like Chinese rhubarb. Magnolia alone is used for diarrhea.


> quote: 1: Ikarashi Y, Yuzurihara M, Sakakibara I, Nakai Y, Hattori N, Maruyama Y. Effects of the extract of the bark of Magnolia obovata and its biphenolic constituents magnolol and honokiol on histamine release from peritoneal mast cells in rats.Planta Med. 2001 Nov;67(8):709-13.2: Shin TY, Kim DK, Chae BS, Lee EJ. Antiallergic action of Magnolia officinalis on immediate hypersensitivity reaction.Arch Pharm Res. 2001 Jun;24(3):249-55.3: Wang JP, Hsu MF, Raung SL, Chen CC, Kuo JS, Teng CM. Anti-inflammatory and analgesic effects of magnolol. Naunyn Schmiedebergs Arch Pharmacol. 1992 Dec;346(6):707-12.4: Tsuruga T, Ebizuka Y, Nakajima J, Chun YT, Noguchi H, Iitaka Y, Sankawa U. Biologically active constituents of Magnolia salicifolia: inhibitors of induced histamine release from rat mast cells.Chem Pharm Bull (Tokyo). 1991 Dec;39(12):3265-71.


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## poet (Nov 17, 2003)

Thanks Mike and eric. To put it into English chronic stress upregulates the immune system which affects mast cells which affects serotonin levels which affects pain perception causes dysregulation?tom


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## eric (Jul 8, 1999)

Stress down regulates. The problem in IBS is both up and down regulations.


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## kel1059 (Feb 28, 2003)

> quote: Mast cell degranulation/histamine release is inhibited by magnolia bark, which also inhibits IgE activity and inflammitory leukotrienes.Magnolia bark also reduces anxiety. The anxiolytic effect is comparable to diazepam (valium), but it takes a few days to kick in. The anti-anxiety action is non-sedating, and longer acting than valium. Magnolia appears in several Chinese formulas for constipation, but this is usually with other laxative herbs like Chinese rhubarb. Magnolia alone is used for diarrhea.


this is the kind of info i look for .........thanks.


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## SpAsMaN* (May 11, 2002)

kel,are you gonna try magnolia?Let me know.I like to be inform about underground trial.Thanks eric but ,i'm have some difficulty to understand all the details of these researchs.


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## poet (Nov 17, 2003)

I think it depends on whether the stress is acute or chronic, and I think the idea that stress upregulates the immune system is a quote from an article that you or Mike posted. Upregulation generally means, I think, that the thermostat is turned down to a lower threshold so that it's more likely to be triggered? Some of the stress vocabulary is unfortunately counterintuitive. It's too bad you don't understand this, frank. Are there some questions you could ask that would help you and others?tom


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## SpAsMaN* (May 11, 2002)

How can i regulate mast cells?Micheal Gherson(top md researcher)suggest his theory on tv; The people have been treated the head for years in ibs cases whithout results,and if ibs was the cause of their stress...Spasman theory;stress cause ibs but not feed it.


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## kel1059 (Feb 28, 2003)

frank,i started TCM --chinese medicine a couple weeks ago and i will ask about this magnolia bark. of course, the hong kong doctor does not speak very good english. he prefers to not talk much or listen much.so far it has been 4 huge batches of herbs that i cook up and drink at one sitting. they give you a shoebox quantity of herbs that taste very bad.(the further i get away from Western Medicine --the better off i am)


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## eric (Jul 8, 1999)

Chronic stress activates and its important to understand what that means in regards to IBS, because its not the kind of stress most people think of when they think stress and emotions them selves are part of the picture, but chronic stress activates the HPA axis and down regulates to the mast cells and they degranulate without a pathogen and release toxins onto the nerves. Foods degranulate mast cells in the gut.The serotonin issue is a different issue in some regards even though both are connected. Mast cells store and release serotonin also, but EC cells store the most serotonin, up to 70 percent. It is the release of serotonin from EC cells that contribute to altered motility and the d right out of the gate from the ACT of Eating. However both cells are important players in IBS. They are also important to Post infectious IBS.There is a lot of interest for a long time now and a ton of work done and more being done on the mast cells and they are looking to see if this has to do with the pain and viceral hypersentivity in IBS, as well as serotonin which is also a neurotransmitter involved in pain. Hence why they use anti d's for pain in IBS.Post infectious IBSGastroenterology. 2003 Dec;125(6):1651-9. Related Articles, Links Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Dunlop SP, Jenkins D, Neal KR, Spiller RC. Wolfson Digestive Diseases Centre, University Hospital, Nottingham, England. BACKGROUND & AIMS: Both psychological and mucosal changes (increased enterochromaffin EC cells and T lymphocytes) have been associated with postinfectious irritable bowel syndrome (PI-IBS). However, previous studies have been underpowered to determine the relative importance of these changes in predicting the development of PI-IBS. Our aim was to prospectively determine the relative importance of both psychological and histologic factors in the development of PI-IBS after Campylobacter infection. METHODS: Questionnaires detailing psychological and bowel symptoms were sent to 1977 patients 3 months after infection. Twenty-eight patients with new-onset PI-IBS, 28 age- and sex-matched patient controls who were asymptomatic after infection, and 34 healthy volunteers underwent rectal biopsy, which was assessed for serotonin-containing EC cells, mast cells, and lamina propria T lymphocytes. RESULTS: PI-IBS, predominantly of the diarrhea-predominant subtype, occurred in 103 of 747 (13.8%) of those infected. EC cell counts per high-power field (hpf) were higher in patients with PI-IBS (35.8 +/- 1.2) compared with patient controls (30.6 +/- 1.9; P = 0.022) and volunteers (29.1 +/- 1.8; P = 0.006). Lamina propria T lymphocytes per hpf were higher in patients with PI-IBS (127.1 +/- 8.7) and patient controls (113.4 +/- 6.2) in contrast to healthy volunteers (97.1 +/- 5.7) (P = 0.006 and P = 0.058, respectively). Anxiety, depression, and fatigue were significantly increased in patients with PI-IBS compared with patient controls. Multivariate analysis indicated that increased EC cell counts and depression were equally important predictors of developing PI-IBS (relative risk, 3.8 and 3.2 for each standard deviation increase in respective values). CONCLUSIONS: Both increased EC cells and depression are important independent predictors of developing PI-IBS. PMID: 14724817


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## kel1059 (Feb 28, 2003)

eric are you making things up to sell tapes?


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## eric (Jul 8, 1999)

Kel, the tapes are a natural, very safe and effective treatment option for IBS and have helped hundreds if not 1000's of people with IBS. There is almost no negative research on HT and IBS and it is almost tailor made for IBS, so I have no idea why you would be agaisnt that or the 20 years of research on HT and IBS showing it is effective for the majority of people? The tapes were here long before you were here helping people and they were here before I was here. What purpose does it sever to bash HT all the time or bring this up all the time. Yes I am a huge fan of HT for IBS and it is argueably the most effective treatment to date for IBS in the research. You would think you would be a fan since it might help people get off drugs like myself and many others for example and that its safe, natural and effective, and hence worth trying. It also can help boost the immune sytem, something else you would think you would be a fan of? But I constantly see you negative about it. You should ask yourself why you feel that way? I wonder how many people don't consider it, when reading all the nasty comments other have made about it over the years, especially at some attempts to get at me, without really studying it and learning about it? Because if you do, you will see what the real deal is with HT and IBS."Why Consider Hypnosis Treatment for IBS?by Olafur S. Palsson, Psy.D.Hypnosis is only one of several approaches to treating irritable bowel syndrome and may not be the most suitable option for all patients (click here for discussion of treatment options for IBS). However, hypnosis treatment has some advantages which makes it an attractive option for many IBS sufferers with chronic and severe symptoms:- It is one of the most successful treatment approaches for chronic IBS. The response rate to treatment is 80% and better in most published studies to date.- The treatment often helps individuals who have failed to get improvements with other methods (see for example: Whorwell et al., 1984, 1987; Palsson et al., 1997, 2000).- It is a uniquely comfortable form of treatment; relaxing, easy and generally enjoyable.- It utilizes the healing power of the person's own mind, and is generally completely without negative side effects.- The treatment sometimes results in improvement in other symptoms or problems such as migraine or tension headaches, along with the improvement in IBS symptoms.- The beneficial effects of the treatment last long after the end of the course of treatment. According to research, individuals who improve from hypnosis treatment for IBS can generally look forward to years of reduced bowel symptoms." http://www.ibshypnosis.com/whyhypnosis.html Gut. 2003 Nov;52(11):1623-9. Related Articles, Links Long term benefits of hypnotherapy for irritable bowel syndrome. Gonsalkorale WM, Miller V, Afzal A, Whorwell PJ. Department of Medicine, University Hospital of South Manchester, Manchester, UK. wgonsalkorale###compuserve.com BACKGROUND AND AIMS: There is now good evidence from several sources that hypnotherapy can relieve the symptoms of irritable bowel syndrome in the short term. However, there is no long term data on its benefits and this information is essential before the technique can be widely recommended. This study aimed to answer this question. PATIENTS AND METHODS: 204 patients prospectively completed questionnaires scoring symptoms, quality of life, anxiety, and depression before, immediately after, and up to six years following hypnotherapy. All subjects also subjectively assessed the effects of hypnotherapy retrospectively in order to define their "responder status". RESULTS: 71% of patients initially responded to therapy. Of these, 81% maintained their improvement over time while the majority of the remaining 19% claimed that deterioration of symptoms had only been slight. With respect to symptom scores, all items at follow up were significantly improved on pre-hypnotherapy levels (p 0.001) and showed little change from post-hypnotherapy values. There were no significant differences in the symptom scores between patients assessed at 1, 2, 3, 4, or 5+ years following treatment. Quality of life and anxiety or depression scores were similarly still significantly improved at follow up (p 0.001) but did show some deterioration. Patients also reported a reduction in consultation rates and medication use following the completion of hypnotherapy. CONCLUSION: This study demonstrates that the beneficial effects of hypnotherapy appear to last at least five years. Thus it is a viable therapeutic option for the treatment of irritable bowel syndrome.also this is one reason why people have problems in the mornings, because that is when there are the highest cortisol levels.The Fight or Flight Response in Irritable Bowel SyndromeOveractivation Linked to Predominance of Diarrhea SymptomsAn intense, powerful "fight-or-flight" response comes in handy when you're running away from a hungry tiger, but it could be the source of misery for people with certain digestive disorders.The chronic gastrointestinal distress of Irritable Bowel Syndrome (IBS) has been linked to "miscommunication" between the gut and the brain. Although it's still unclear just exactly how a glitch in gut-brain interaction sparks specific symptoms, a recent study has uncovered one important potential mechanism in a subgroup of patients.In patients with IBS who regularly experience diarrhea, pain, and other symptoms soon after eating, an "overdominant" sympatheti nervous system - signaled in part by the heightened release of the stres hormone cortisol after eating - may play a key role in triggering their symptoms. Researchers evaluated a group of 24 patients with IBS and a group of healthy controls, measuring their salivary cortisol levels, their heart rates, and their heart rate variabilities at different times of the day.Compared to the controls and to IBS patients with constipation, IBS patients with chronic food-induced diarrhea "demonstrated a significant increase in cortisol" soon after eating - with levels nearly doubling. This subset of patients also showed a more dominant sympathetic nervous system response, as evidenced by their heart rate variability ratios.The sympathetic nervous system tends to mobilize the body's stimulatory "fight-or-flight" response. Normally it's kept in check by the dampening effects of the parasympathetic nervous system. In patients with IBS with diarrhea, however, this muting response (mediated by the vagus nerve) appears weaker - a condition called "vagal withdrawal." "Notably, this vagal withdrawal was significantly associated with patients' reports of gastrointestinal symptoms," the researchers pointed out. These included bloating, abdominal pain, indigestion, and heartburn.A heightened, stimulatory stress response, characterized by overactivation of both the HPA-axis and sympathetic nervous system, may be triggered by "abnormal ascending feedback from the gut," the researchers speculated.NOTE: Two functional assessments help evaluate important dynamics of the gut-brain connection in stress-related gastrointestinal disorders.The Adrenocortex Stress Profile helps to pinpoint HPA-axis abnormalities affecting the body's response to stress, measuring salivary cortisol levels at four times during the day. A single DHEA assay and a DHEA/cortisol ratio is included to evaluate adrenal balance. http://www.gsdl.com/news/connections/vol12...30.html#anchor2


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## kel1059 (Feb 28, 2003)

settle down. i am a supporter of this method. tapes may work for some people also.


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## kel1059 (Feb 28, 2003)

but i think it is only part of the answer for us. for some people it may be a very small answer and for others it can be a great help.


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## m_m_forth (Oct 21, 2003)

I think I speak for others as well when I say, I'll take whatever I can get. Right now I will just be happy if I can kick my D attacks (doing good so far). I have given up hoping for a cure or to be totally normal. In reality, everyone has their own problems. I think I will just be thankful that all I have is IBS, and don't have cancer, or Crohns, or something else devastating. I am a believer in HT for IBS. I think many of us have the chronic stress thing in common. Although, as I have said before, I think there are subtypes of IBS (many different causes for similar symptoms). I predict that future research will reveal this. Afterall, look how many other causes mirror IBS symptoms (cancer, Crohns, colitis). Researchers are really just beginning putting the puzzle together here. So why don't we all just do what works for ourselves, share our ideas, and entertain the idea that many different actions can be helpful for our symptoms? Let's let the research speak for itself. That's my 2 cents.


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## SpAsMaN* (May 11, 2002)

It is better to not be sick with the western medecine.BE VERY CAREFUL BEFORE TO SHARES THE CONTROL OF YOUR BODY AND HEALTH BY ANY HEALTH CARE PROVIDER.


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## kel1059 (Feb 28, 2003)

WARNING: Western medicine can be dangerous to your health (what do you think frank.. should the surgeon general warn us about it?)maybe.realist, you have given up hope of being normal. how long have you suffered? what is helping you


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## floridian2 (Dec 1, 2003)

The Chinese name for magnolia bark is houpu (don't have the Chinese character handy). Here is a link to a good overview: http://www.itmonline.org/arts/magnolia.htm


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## kel1059 (Feb 28, 2003)

chinese herbal medicine is interesting. when i went i walked out of there with almost a shoebox full quantity of herbs. all of which were to be made into an 8oz tea to be consumed at one sitting. a half gallon of water was boiled down to 8 oz. the tea tasted like a dirt/compost mix.


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## SpAsMaN* (May 11, 2002)

forget it kel you gonna not gonna be warn!Here in canada it's the third world,because it's free for everybody,you're treat like a homeless.We open you and when you wake up it's too late,now go see your mom and cry.Don't even think about criminal procedure requestthese people are god send!If you're name is Bill Gates you can make this people eat theirs socks.But what you can achievein money when a MEDICAL ERROR have been proven is a fraction of what is given in u.s.I talk to a girl who wake during a nose job!She had a heart attack rigth away.Very scary!


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## kel1059 (Feb 28, 2003)

i asked about hou po and all i got was a grunt. so much for the alt healers being all touchy feely and making us better that way.


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