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To further the discussion set forth in the second reference above, a little taste of the fruits of the investigations of allergists and immunologists into the role of inflammatory mediators in IBS patients...put in the frame of reference of the frequency of depression and other aberrant behaviors seen in IBS patients. As the article suggests, the gastroneuroimmune system is wholly integrated and interdependent. Study of the system to understand its total interdependency should be inclusive, not exclusive, of all the functional componenets of the system and what has been recently found. And not so recently suspected! Tis ofetn is not done yet. A Case in point... ________________________________Neuroendocrinol Lett 1999;20(1-2):11-17Activation of the inflammatory response system: A new look at the etiopathogenesis of major depression.van West D, Maes M.Clinical Research Center for Mental Health (CRC-MH), Antwerp, Belgium.Major depression is accompanied by various direct and indirect indicators of a moderate activation of the inflammatory response system (IRS). Increased production of proinflammatory cytokines, such as interleukin-1 (IL-1), IL-6 and interferon (IFNgamma), may play a crucial role in the immune and acute phase response in depression. Lower serum zinc and changes in the erythron are indirect indicators of IRS activation in depression. The reciprocal relationships between IRS activation and hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity, alterations in HP thyroid (HPT)-axis function and the availability of tryptophan to the brain led us to hypothesize that these neuroendocrine changes in depression are indicators of IRS activation and that a combined dysregulation of the IRS, the turnover of serotonin (5-HT) and the HPA-axis is an integral component of depression. The IRS activation model of depression provides an explanation for the psycho-social (external stress) as well as organic (internal stress) etiology of major depression. Antidepressive treatments with various antidepressive agents, including SSRIs, tricyclic and heterocyclic antidepressants, have in vivo and in vitro negative immunoregulatory effects, suggesting that their antidepressant efficacy may be attributed, in part, to their immune effects. _________________________________Interestingly, the mediators cited, for example, are mediators associated with the innate immune response, and spewed by macrophages when activated as part of the acute-phase inflammatory response (which is only supposed to be provoked by pathogens)BUT which has been seen in IBS patients to be provocable with various dietary challenges specific to each patient. (see the mast cell thread for more). Note the small bowel findings of Tornbloom in the same context and the context of the informaton which follows from Bengtson vis a vis what he just found but did not published yet. __________________________________HISTOPATHOLOGICAL FINDINGS IN JEJUNUM OF PATIENTS WITH SEVERE IRRITABLE BOWEL SYNDROMETornbloom H, Lindberg, G, Nyberg B, Veress BUniversity if Lund, Malmo, SwedenDIGESTIVE DISEASE WEEK, MAY 21-24, 2000, SAN DIEGO CALIFORNIA(6) patients with documented severe IBS which met all ROME criteria and normal antroduodenal manometry (thus not misdiagnosed cases of idiopathic intestinal pseudo-obstruction) where laparoscopized to the level of the jejunum. In all (6) when jejunal biopsies were obtained inflammatory infiltration of lymphocytes was found in the myenteric plexus (the network of nerve fibers and neuroganglie found between the longitudinal and circular layers of smooth muscle of the intestine). The lymphocytes were situated in periganglionic and intraganglionic locations. (4) patients showed hypertrophy of the longitudinal muscle layer, and (5) patients showed abnormailities of the interstitial Cells of Cajal **[Note**Synapse like contacts between ICC and nerve endings are characteristic, ICC make contact with smooth muscle cells by means of close appositions or gap junctions. ICC are crucial in generation of slow waves and in neural transmission in the gut.] ________________________________RECENT CORRESWPONDENCE RECEIVED BY EMAIL SEPTEMBER 15, 2001 BETWEEN MYSELF AND PROF BENGTSSON, SAHLGRENS MEDICAL UNIVERITY, GOTEBORG SWEDEN WHO PIONEERED JEJUNAL ISOLATION STUDIES IN 1994 onoing correspondence on protocols for identification of dietary symptomologic provocation and immunologic markers:Dear Mr Hoffman, Thank your for your kind letter. I think you have seen my papers from 1996and 1997 when we studied allergy-like inflammation in a closed segment in jejunum. When [we]challenged with different staple foods and could show high levels of inflammatory mediators suggesting allergy-like inflammation. Most of these adult patients had IBS-likesymptoms with negative skin prick test and RAST but DBPCFC were positive. However, the method was time-consuming and expensive so we went on with immunohistocheminstry methods with biopsies from duodenum before and during challenges.In a near future we hope to publish our results. Even here we can show an allergy-like inflammation during challenges with parameters like Il-4, IFN-gamma, CD3, CD4, CD8 and IgE.Just now we have a lot of plans and I am afraid that, just now, other activities are too much for us.I hope we can keep contact and later on discuss how to develop better methods to investige patients with food problems. Looking for your comments.Sincerely YoursUlf BengtssonMD, PhD ______________________________IL-4 is released by specific activated lymphocytes...note lymphocyte activation sigsn noted in Tornblooms biopsies...Interferon Gamma is expressed by CD8 t-lymphocytes and activates macrophages...IL8 (see above) is expressed by mast cells in the primary response and promotes the influx of various leukocytes to the site of activation.The common thread of proinflammatory mediators running through the immunologic investigations of people with IBS d and cyclic symptoms sets, which is also often associated systemic symptoms including depression, all of which are known effects of specific mediators which can be recovered from the small bowel of these patients whose symptoms and reactivity are provocable by various food challenges, has been clearly observed and is consistent between different investigators. There are myriad other studies over the years which contain elements of this part of the puzzle, which continue to clarify WHAT is happening which can provoke the symptoms. Again, at least prophylaxis is possible if you use the information correctly.The ultimate question of WHY is the immune system reacting the way it does in the small bowel and microvasculature may involve, as has been suggested by some, an aberration in specific CNS centers as one element among many if you study the toal picture of immuocyte managment by the body.But it may be that Bengtsson has also found (several times) the more likely primary culprit which has eluded dtection all these years since he apparently hides down there in your small bowel and does not show up with conventional tests for him: it may be specifc IgE after all, BUT a form of localized immunologic mechanism which now needs to be studied as it has not been observed before, only suspected based upon what could be observed. Since these Swedish investigators keep recovering it in the small bowel even though the selected patients are all RAST and SPT negative (having found those with obvious food allergy comorbidity and removed them from each investigation) but oral challenge positive.This mechanism of possible localized response was first suspected ALL THE WAY BACK IN 1980
when specific prostaglandin abnormalites were found in stool cultures of certain IBS patients and they responded to the prostaglndin inhibitors such as Indocin: _________________________________Adv Prostaglandin Thromboxane Res 1980;8:1627-31 An approach to evaluation of local intestinal PG production and clinical assessment of its inhibition by indomethacin in chronic diarrhea. Bukhave K, Rask-Madsen J No abstract ON LINE..Summary of Findings:The connection between gut motility and prostaglandin release was studied. PGE2 levels in the jejunal secretions IBS patients were elevated in 10 of 17 with cyclic IBS (D & C) and in "gluten enteropathy". Six IBS patients treated with indomethacin had a 50% reduction in stool volume and frequency. And withdrawal of the indocin caused the symptoms to return.Due to the absence of indicators of Type I inflammatory-allergic response, the authors said the findings suggested localized or gut-wall reactions . ________________________________________Those astute enough to suspect that there is indeed a common thread, which links not only the localized symptoms and systemic symptoms but the interdependent psychologic symptoms, will see where the link has remained, hiding away in plain site as nobody went looking for it, for over 20 years. What evokes great interest, before even speculating about WHY this aberrant neuroimmune provocation actually occurs (and there seems to be about 4 primary possibilities), would be considering each of the proinflammatory mediators being expressed in the reaction, their specific effects, and which of them either cross the blood-brain barrier under conditions of homeostasis and which mediators can and do cross the blood brain barrier once an inflammatory reaction occurs and BBB permeability, like gut vascular permeability, is altered by certain mediators which peform that function thus allowing other specific mediators and cells to extravasate (slip out of the capillary into the surroundin extracellular fluid). Since there are over 100 known proinflammatory mediators known so far which can be involved in different types of reactiosn thsi will be a tall-order. So far only relatively narrow assays have been done as you see (this is not cheap and easy work). In future studies the mediator hunt must be widened.A very interesting and compelling post, especially when put in the context of other less obvious but just as concrete information that has been isolated and published over the last two decades.Eat well. Think well. Be wellMNL
 

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To further the discussion set forth in the second reference above, a little taste of the fruits of the investigations of allergists and immunologists into the role of inflammatory mediators in IBS patients...put in the frame of reference of the frequency of depression and other aberrant behaviors seen in IBS patients. As the article suggests, the gastroneuroimmune system is wholly integrated and interdependent. Study of the system to understand its total interdependency should be inclusive, not exclusive, of all the functional componenets of the system and what has been recently found. And not so recently suspected! Tis ofetn is not done yet. A Case in point... ________________________________Neuroendocrinol Lett 1999;20(1-2):11-17Activation of the inflammatory response system: A new look at the etiopathogenesis of major depression.van West D, Maes M.Clinical Research Center for Mental Health (CRC-MH), Antwerp, Belgium.Major depression is accompanied by various direct and indirect indicators of a moderate activation of the inflammatory response system (IRS). Increased production of proinflammatory cytokines, such as interleukin-1 (IL-1), IL-6 and interferon (IFNgamma), may play a crucial role in the immune and acute phase response in depression. Lower serum zinc and changes in the erythron are indirect indicators of IRS activation in depression. The reciprocal relationships between IRS activation and hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity, alterations in HP thyroid (HPT)-axis function and the availability of tryptophan to the brain led us to hypothesize that these neuroendocrine changes in depression are indicators of IRS activation and that a combined dysregulation of the IRS, the turnover of serotonin (5-HT) and the HPA-axis is an integral component of depression. The IRS activation model of depression provides an explanation for the psycho-social (external stress) as well as organic (internal stress) etiology of major depression. Antidepressive treatments with various antidepressive agents, including SSRIs, tricyclic and heterocyclic antidepressants, have in vivo and in vitro negative immunoregulatory effects, suggesting that their antidepressant efficacy may be attributed, in part, to their immune effects. _________________________________Interestingly, the mediators cited, for example, are mediators associated with the innate immune response, and spewed by macrophages when activated as part of the acute-phase inflammatory response (which is only supposed to be provoked by pathogens)BUT which has been seen in IBS patients to be provocable with various dietary challenges specific to each patient. (see the mast cell thread for more). Note the small bowel findings of Tornbloom in the same context and the context of the informaton which follows from Bengtson vis a vis what he just found but did not published yet. __________________________________HISTOPATHOLOGICAL FINDINGS IN JEJUNUM OF PATIENTS WITH SEVERE IRRITABLE BOWEL SYNDROMETornbloom H, Lindberg, G, Nyberg B, Veress BUniversity if Lund, Malmo, SwedenDIGESTIVE DISEASE WEEK, MAY 21-24, 2000, SAN DIEGO CALIFORNIA(6) patients with documented severe IBS which met all ROME criteria and normal antroduodenal manometry (thus not misdiagnosed cases of idiopathic intestinal pseudo-obstruction) where laparoscopized to the level of the jejunum. In all (6) when jejunal biopsies were obtained inflammatory infiltration of lymphocytes was found in the myenteric plexus (the network of nerve fibers and neuroganglie found between the longitudinal and circular layers of smooth muscle of the intestine). The lymphocytes were situated in periganglionic and intraganglionic locations. (4) patients showed hypertrophy of the longitudinal muscle layer, and (5) patients showed abnormailities of the interstitial Cells of Cajal **[Note**Synapse like contacts between ICC and nerve endings are characteristic, ICC make contact with smooth muscle cells by means of close appositions or gap junctions. ICC are crucial in generation of slow waves and in neural transmission in the gut.] ________________________________RECENT CORRESWPONDENCE RECEIVED BY EMAIL SEPTEMBER 15, 2001 BETWEEN MYSELF AND PROF BENGTSSON, SAHLGRENS MEDICAL UNIVERITY, GOTEBORG SWEDEN WHO PIONEERED JEJUNAL ISOLATION STUDIES IN 1994 onoing correspondence on protocols for identification of dietary symptomologic provocation and immunologic markers:Dear Mr Hoffman, Thank your for your kind letter. I think you have seen my papers from 1996and 1997 when we studied allergy-like inflammation in a closed segment in jejunum. When [we]challenged with different staple foods and could show high levels of inflammatory mediators suggesting allergy-like inflammation. Most of these adult patients had IBS-likesymptoms with negative skin prick test and RAST but DBPCFC were positive. However, the method was time-consuming and expensive so we went on with immunohistocheminstry methods with biopsies from duodenum before and during challenges.In a near future we hope to publish our results. Even here we can show an allergy-like inflammation during challenges with parameters like Il-4, IFN-gamma, CD3, CD4, CD8 and IgE.Just now we have a lot of plans and I am afraid that, just now, other activities are too much for us.I hope we can keep contact and later on discuss how to develop better methods to investige patients with food problems. Looking for your comments.Sincerely YoursUlf BengtssonMD, PhD ______________________________IL-4 is released by specific activated lymphocytes...note lymphocyte activation sigsn noted in Tornblooms biopsies...Interferon Gamma is expressed by CD8 t-lymphocytes and activates macrophages...IL8 (see above) is expressed by mast cells in the primary response and promotes the influx of various leukocytes to the site of activation.The common thread of proinflammatory mediators running through the immunologic investigations of people with IBS d and cyclic symptoms sets, which is also often associated systemic symptoms including depression, all of which are known effects of specific mediators which can be recovered from the small bowel of these patients whose symptoms and reactivity are provocable by various food challenges, has been clearly observed and is consistent between different investigators. There are myriad other studies over the years which contain elements of this part of the puzzle, which continue to clarify WHAT is happening which can provoke the symptoms. Again, at least prophylaxis is possible if you use the information correctly.The ultimate question of WHY is the immune system reacting the way it does in the small bowel and microvasculature may involve, as has been suggested by some, an aberration in specific CNS centers as one element among many if you study the toal picture of immuocyte managment by the body.But it may be that Bengtsson has also found (several times) the more likely primary culprit which has eluded dtection all these years since he apparently hides down there in your small bowel and does not show up with conventional tests for him: it may be specifc IgE after all, BUT a form of localized immunologic mechanism which now needs to be studied as it has not been observed before, only suspected based upon what could be observed. Since these Swedish investigators keep recovering it in the small bowel even though the selected patients are all RAST and SPT negative (having found those with obvious food allergy comorbidity and removed them from each investigation) but oral challenge positive.This mechanism of possible localized response was first suspected ALL THE WAY BACK IN 1980
when specific prostaglandin abnormalites were found in stool cultures of certain IBS patients and they responded to the prostaglndin inhibitors such as Indocin: _________________________________Adv Prostaglandin Thromboxane Res 1980;8:1627-31 An approach to evaluation of local intestinal PG production and clinical assessment of its inhibition by indomethacin in chronic diarrhea. Bukhave K, Rask-Madsen J No abstract ON LINE..Summary of Findings:The connection between gut motility and prostaglandin release was studied. PGE2 levels in the jejunal secretions IBS patients were elevated in 10 of 17 with cyclic IBS (D & C) and in "gluten enteropathy". Six IBS patients treated with indomethacin had a 50% reduction in stool volume and frequency. And withdrawal of the indocin caused the symptoms to return.Due to the absence of indicators of Type I inflammatory-allergic response, the authors said the findings suggested localized or gut-wall reactions . ________________________________________Those astute enough to suspect that there is indeed a common thread, which links not only the localized symptoms and systemic symptoms but the interdependent psychologic symptoms, will see where the link has remained, hiding away in plain site as nobody went looking for it, for over 20 years. What evokes great interest, before even speculating about WHY this aberrant neuroimmune provocation actually occurs (and there seems to be about 4 primary possibilities), would be considering each of the proinflammatory mediators being expressed in the reaction, their specific effects, and which of them either cross the blood-brain barrier under conditions of homeostasis and which mediators can and do cross the blood brain barrier once an inflammatory reaction occurs and BBB permeability, like gut vascular permeability, is altered by certain mediators which peform that function thus allowing other specific mediators and cells to extravasate (slip out of the capillary into the surroundin extracellular fluid). Since there are over 100 known proinflammatory mediators known so far which can be involved in different types of reactiosn thsi will be a tall-order. So far only relatively narrow assays have been done as you see (this is not cheap and easy work). In future studies the mediator hunt must be widened.A very interesting and compelling post, especially when put in the context of other less obvious but just as concrete information that has been isolated and published over the last two decades.Eat well. Think well. Be wellMNL
 

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PS...oh yeah this was kind of cool too all you IBS/Fibro Comorbids.... __________________________________Psychoneuroendocrinology 1999 May;24(4):371-83 RThe immune-inflammatory pathophysiology of fibromyalgia: increased serum soluble gp130, the common signal transducer protein of various neurotrophic cytokines.Maes M, Libbrecht I, Van Hunsel F, Lin AH, De Clerck L, Stevens W, Kenis G, de Jongh R, Bosmans E, Neels H.University Department of Psychiatry, Clinical Research Center for Mental Health (CRC-MH), Antwerp, Belgium. m.maes###unicall.beFibromyalgia is a chronic, painful musculoskeletal disorder characterized by widespread pain, pressure hyperalgesia, morning stiffness and by an increased incidence of depressive symptoms. The etiology, however, has remained elusive. The aim of the present study was to examine the inflammatory response system (IRS) in fibromyalgia. Serum interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), sgp130, sIL-1R antagonist (IL-1RA) and sCD8 were determined in 33 healthy volunteers and in 21 fibromyalgia patients, classified according to the American College of Rheumatology criteria. Severity of illness was measured with several pain scales, dolorimetry and the Hamilton Depression Rating Scale (HDRS). Serum sgp130 was significantly higher and serum sCD8 significantly lower in fibromyalgia patients than in healthy volunteers. Serum sIL-6R and sIL-1RA were significantly higher in fibromyalgia patients with an increased HDRS score (> or = 16) than in normal volunteers and fibromyalgia patients with a HDRS score < 16. In fibromyalgia patients, an important part of the variance in sCD8 (50.3%) and IL-1RA (19.3%) could be explained by the HDRS score; 74.3% of the variance in sIL-6R was explained by the combined effects of pain symptoms and the HDRS score; and 25.9% of the variance in serum sgp130 was explained by stiffness. The results support the contention that pain and stiffness in fibromyalgia may be accompanied by a suppression of some aspects of the IRS and that the presence of clinically significant depressive symptoms in fibromyalgia is associated with some signs of IRS activation. ___________________________________MNL
 

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PS...oh yeah this was kind of cool too all you IBS/Fibro Comorbids.... __________________________________Psychoneuroendocrinology 1999 May;24(4):371-83 RThe immune-inflammatory pathophysiology of fibromyalgia: increased serum soluble gp130, the common signal transducer protein of various neurotrophic cytokines.Maes M, Libbrecht I, Van Hunsel F, Lin AH, De Clerck L, Stevens W, Kenis G, de Jongh R, Bosmans E, Neels H.University Department of Psychiatry, Clinical Research Center for Mental Health (CRC-MH), Antwerp, Belgium. m.maes###unicall.beFibromyalgia is a chronic, painful musculoskeletal disorder characterized by widespread pain, pressure hyperalgesia, morning stiffness and by an increased incidence of depressive symptoms. The etiology, however, has remained elusive. The aim of the present study was to examine the inflammatory response system (IRS) in fibromyalgia. Serum interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), sgp130, sIL-1R antagonist (IL-1RA) and sCD8 were determined in 33 healthy volunteers and in 21 fibromyalgia patients, classified according to the American College of Rheumatology criteria. Severity of illness was measured with several pain scales, dolorimetry and the Hamilton Depression Rating Scale (HDRS). Serum sgp130 was significantly higher and serum sCD8 significantly lower in fibromyalgia patients than in healthy volunteers. Serum sIL-6R and sIL-1RA were significantly higher in fibromyalgia patients with an increased HDRS score (> or = 16) than in normal volunteers and fibromyalgia patients with a HDRS score < 16. In fibromyalgia patients, an important part of the variance in sCD8 (50.3%) and IL-1RA (19.3%) could be explained by the HDRS score; 74.3% of the variance in sIL-6R was explained by the combined effects of pain symptoms and the HDRS score; and 25.9% of the variance in serum sgp130 was explained by stiffness. The results support the contention that pain and stiffness in fibromyalgia may be accompanied by a suppression of some aspects of the IRS and that the presence of clinically significant depressive symptoms in fibromyalgia is associated with some signs of IRS activation. ___________________________________MNL
 
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