Crohns Disease Homeopathic Cure

Cured My Crohns

If you've ever gotten the fateful diagnosis you've got Crohns, you will know the massive upset that it can have on your way of life and how you feel about yourself and your relationship to other people. If you talk to your doctor about natural diets or some other method of curing your Crohns disease they will tell you that there is no way to fix it. However, there is often more to the story than modern medicine will tell you. New Age medicine is not a bunch of nonsense that hokey people subscribe to; New Age medicine fills in the gaps of knowledge that we have with modern medicine and helps us understand what is going on with our bodies. You will learn how to cure Crohns from someone who has cured it himself and has lived for over 10 years completely free of disease!

Cured My Crohns Overview

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Identification of ATG16L1 and IRGM1 as Crohns Disease Susceptibility Genes

The genetic loci for both ATG16L1 and IRGM1 were linked to Crohn's disease by genome-wide association studies in which genetic variations between Crohn's disease patients and controls were analyzed using gene chips containing 10,000 known single nucleotide polymorphisms (SNPs) across the human genome (The Wellcome Trust Case Control Consortium 2007 Rioux et al. 2007 Hampe et al. 2007 Parkes et al. 2007 McCarroll et al. 2008 Barrett et al. 2008). For ATG16L1, the genetic linkage is stronger for patients that primarily have ileal disease, which is not necessarily true for the other susceptibility loci. This genetic linkage is attributed to a single SNP (rs2241880) that leads to a threonine to alanine amino acid substitution in a region of the Atg16L1 protein without a known function. The rs2241880 SNP is very common and can be found in as many as 50 of healthy individuals depending on the population examined (The Wellcome Trust Case Control Consortium 2007 Rioux et al. 2007 Hampe et al....

Mice with Reduced Atg16L1 Expression Reproduce Aspects of Crohns Disease Pathology and Reveal a Cellular Target for the

While the Atg16L1 KO model is ideal for studying the role of Atg16L1 in hemat-opoietic lineages, perinatal lethality of these mice does not allow examination of the role of Atg16L1 in the small intestine in adult mice. The newly developed Atg16L1HM mice are therefore a unique tool since, instead of relying on a lineage-specific deletion of the gene, there is a systemic reduction of the protein (Cadwell et al. 2008a). As it is unlikely that Atg16L1 function is completely abolished in humans carrying the Crohn's disease risk allele (Kuballa et al. 2008), this model may be more reflective of the disease predisposition state. Indeed, the autophagy defect in the intestinal epithelium of these mice is not as severe as mice with a complete deletion of Atg5 in this tissue (Cadwell et al. 2008a). Histological examination of the small intestine from Atg16L1HM mice led to the identification of a previously unknown human Crohn's disease pathology striking morphological, functional, and...

Crohns Disease

Crohn's disease (CD) is chronic inflammation of the alimentary canal, mostly the bowel, that usually first appears in children or young adults. It is relevant to this review because of a distinctive feature, the selective hypertrophy of mesenteric adipose tissue around the inflamed area of the intestine, known as fat wrapping, first identified by Crohn himself (133). It appears early in the course of the disease and persists, even though nearly all patients become thin following prolonged disruption of appetite, digestion, and absorption (134). CD thus shares with HARS the peculiarity of selective expansion of certain adipose depots while others are depleted. There may also be some

Role of Autophagy and Autophagy Genes in Inflammatory Bowel Disease

3 Autophagy and Crohn's 3.1 Identification of ATG16L1 and IRGM1 as Crohn's Disease 4.3 Mice with Reduced Atg16L1 Expression Reproduce Aspects of Crohn's Disease Pathology, and Reveal a Cellular Target for the Role of Atg16L1 in Crohn's Abstract Polymorphisms associated with two genes in the autophagy pathway, ATG16L1 and IRGM1, have been implicated in susceptibility to Crohn's disease, an idiopathic inflammatory disease typically involving the gastrointestinal tract. The intestinal mucosa is a site of careful immune regulation where the epithelium and immune cells encounter pathogens as well as a robust and diverse population of indigenous microbes that are predominately bacteria. Since the role of autophagy in immunity is broad and expanding, it is unclear which downstream functions of autophagy and which cell types are the key factors in Crohn's disease susceptibility. This chapter reviews the recent literature on the roles of ATG16L1 and 1RGM1 in the autophagy pathway,...

Murine Models of Colitis

As a basis for understanding the potential role of autophagy genes in inflammatory bowel disease, we will first review studies of inflammatory bowel disease pathogenesis and causation performed in animals prior to recent analyses of mice lacking or expressing low levels of autophagy proteins. It is clear that a fundamental understanding of the functions of the intestinal epithelium and immune system, as well as the intestinal response to injury, is a prerequisite for comprehending potentially aberrant inflammatory responses in diseases such as Crohn's disease or ulcerative colitis. Since genetic background can influence the degree of physical damage, inflammation, and efficiency of recovery, one can study the role of individual genes in the colonic injury response using this model (Xavier and Podolsky 2007). For example, mice containing a mutation in the Crohn's disease susceptibility gene NOD2 have been reported to be hypersensitive to damage caused by DSS (Maeda et al. 2005)....

Murine Models for Disease of the Small Intestine

Important for the Crohn's disease field, only three murine genetic models display an inflammatory response in the distal small intestine. This is in striking contrast to the many models available for studying colitis (Xavier and Podolsky 2007 Strober et al. 2002). In the TNFAAU model, the AU-rich region within the 3'UTR of TNF-a is deleted, leading to increased stability of the mRNA for this inflammatory cytokine (Kontoyiannis et al. 1999). TNF-a is one of the major inflammatory cytokines implicated in Crohn's disease pathogenesis, and it is an effective therapeutic target in human Crohn's disease (Targan et al. 1997). Predictably, these mice develop chronic systemic inflammation that includes the small intestine. This model is designed to examine the effects of TNF-a overexpression rather than the events leading to the TNF-a response. The SAMP1 Yit mouse has also been used as a Crohn's disease model. SAMP1 Yit mice were generated by selecting mice that spontaneously develop skin...

The Role of Bacteria in Inflammatory Bowel Disease

Both the epidemiology and the literature presented above raise the obvious question of whether a specific bacterial pathogen causes Crohn's disease. Many groups have attempted to implicate a pathogen through indirect association studies using statistical data (Pineton de et al. 2008). These studies most often attempt to identify the etiological agent long after patients have been diagnosed with the disease. It is therefore possible that the pathogen has already been cleared or is limited to a low level of replication at the time of the investigation. This concern, as well as the heterogeneity of the disease, may account for the failure, to date, to identify a pathogen that causes Crohn's disease (Pineton de et al. 2008). Instead of invoking a single bacterial species as a cause for Crohn's disease, an important alternative hypothesis has been that Crohn's disease is induced by a shift in the commensal intestinal bacterial population, known as dysbiosis. Dysbiosis could potentially be...

Unique Properties of Autolysosomes in Microbial Killing

Initial progress in this direction has been made using M. tuberculosis in a study in which Alonso et al. (Alonso et al. 2007) showed that ubiquitin fragments generated by ubiquitin digestion in autophagosomes endow lysosomes with higher mycobactericidal capacities. This is in keeping with the earlier reports that ubiquitin fragments generally possess antimicrobial properties (Kieffer et al. 2003), although how they were delivered to pathogens was not known. The experimental evidence indicates that autophagy, after capturing cytosolic ubiquitin or ubiquitinated proteins or their aggregates, proteolytically generates ubiquitin fragments during maturation into autolysosomes, and that these fragments are delivered (directly or indirectly) to intracellular M. tuberculosis to enhance its killing. Whether ubiquitin fragments are produced upon the induction of autophagy beforehand or are produced in the same compartment in which M. tuberculosis resides in cells activated for autophagy is not...

The Role of Atg16L1 in Autophagy

An important remaining question regarding the role of Atg16L1 in autophago-some formation is how it is targeted to the nascent autophagosome. In yeast, the isolation membrane is generated from an organelle termed the pre-autophagosomal structure (PAS), and only one autophagosome is generated at a time (Reggiori and Klionsky 2005). In contrast, mammalian cells do not have a well-defined PAS and the origin of the autophagosome is still controversial (Axe et al. 2008). During the starvation response, an indiscriminate engulfment of cytoplasm may be sufficient to maintain cell viability. However, other situations may require the engulfment of specific cytoplasmic constituents such as mitochondria, bacteria, parasites, viruses, intracellular membranes, or proteins. Perhaps this requirement for specificity is greater in higher-order organisms that do not have the cytoplasm-to-vacuole trafficking (CVT) pathway that is important for selective autophagy in yeast (Reggiori and Klionsky 2005)....

Clinical Aspects of Inflammatory Bowel Disease in Humans

Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease. Both are associated with high morbidity and their pathogenesis has been the subject of many excellent review articles (Xavier and Podolsky 2007 Cho 2008 Ferguson et al. 2007 Pineton de et al. 2008 Neuman 2007). The incidence of Crohn's disease has risen in several regions of the globe, suggesting a strong environmental contribution to disease in addition to an undisputed heritable component (Xavier and Podolsky 2007 Ferguson et al. 2007). The incidence of inflammatory bowel disease is highly variable and can be as high as one in 250 people in certain countries including the United States and the United Kingdom (Ferguson et al. 2007). Both Crohn's disease and ulcerative colitis are characterized by chronic and relapsing inflammation of the intestinal mucosa and typically cause clinical symptoms of abdominal pain, severe diarrhea, vomiting, and weight loss. Many features distinguish Crohn's...

Two Mouse Models to Examine Atg16L1 Function In Vivo

The human genetic data and our expanding understanding of the roles of ATG16L1 and IRGM1 support a model in which autophagy contributes to Crohn's disease susceptibility, but also leave open critical questions, including what intestinal or immune cell-types have altered function when either ATG16L1 or IRGM1 are altered, and what functional abnormalities are present in such cells. Given the strong associations between bacteria and intestinal inflammation, are the effects of autophagy genes in Crohn's disease related only to clearance of intracellular bacteria, or are there additional alterations in cells with aberrant Atg16L1 or IRGM1 expression function that might contribute to the pathogenesis of Crohn's disease Two distinct

Bacterial Autophagy in Inflammatory Bowel Disease

Inflammatory bowel disease is a chronic disorder caused by abnormal inflammation in the intestinal tract. Ulcerative colitis and Crohn's disease (CD) are the two major forms of inflammatory bowel disease (Podolsky 2002 Mizoguchi and Mizoguchi 2008). Ulcerative colitis is most often restricted to the colon, while CD involves patchy inflammation throughout the gastrointestinal tract (Xavier and Podolsky 2007). The pathogenesis of these disorders is now believed to involve multiple factors, including environmental conditions, genetic composition of the individual, and bacterial infection (Podolsky 2002 Xavier and Podolsky 2007). Readers are directed to several excellent reviews on the pathogenesis of inflammatory bowel disease by Podolsky (2002), Xavier and Podolsky (2007) and Mizoguchi and Mizoguchi (2008). Here we will focus on the current understanding of autophagy in CD, especially bacteria-related autophagy.

Response and Increased Expression of the Proinflammatory Cytokine IL1fi in Macrophages

In contrast to previous reports from studies in cell lines (Xu et al. 2007 Delgado et al. 2008), TLR ligands did not induce autophagy in primary macrophages (Saitoh et al. 2008). This underlines the importance of studies in nontransformed primary cells for defining the role of autophagy in immunity and pathogenesis (Virgin 2008 Zhao et al. 2007, 2008 Lee et al. 2007). Thus, not all TLRs are strong inducers of autophagy in macrophages in physiological settings. Instead, the autophagy pathway plays a novel and critical role in regulating the TLR-induced inflammatory response (Saitoh et al. 2008). The absence of Atg16L1, or inhibition of the autophagy pathway by other means, leads to an uncontrolled excess production of the proinflammatory cytokines IL-ip and IL-18 in response to TLR4 activation. This represents a gain of function in autophagy-deficient primary macrophages. Interestingly, exposure of Atg16L1 -deficient macrophages to several noninvasive bacteria found in the gut elicits...

Conclusion and Future Perspectives

Fig. 3 Mutation of autophagy genes leads to striking abnormalities in key cell types implicated in intestinal inflammation. Macrophages serve a critical role in mucosal immunity by secreting cytokines and other regulatory molecules that shape the immune environment. Macrophages can also phagocytose and destroy bacteria that inappropriately penetrate the epithelial wall. In addition to a failure to control intracellular bacterial replication through classical autophagy (reviewed in other chapters), autophagy mutant macrophages produce increased amounts of reactive oxygen species (ROS) and the proinflammatory cytokines IL-ip and IL-18 (Saitoh et al. 2008). Paneth cells are highly specialized intestinal epithelial cells located at the crypt base. Paneth cells package antimicrobial factors in granules and, upon stimulation, secrete the granule contents into the intestinal lumen. In autophagy mutant Paneth cells, organelle degeneration is accompanied by granule morphology and secretion...

Macroautophagy in Epithelial Cells

4.6.2.2 Association Between Macroautophagy Regulation and Crohn's Disease A possible role for macroautophagy in the maintenance of immune homeostasis in the gut has been highlighted by recent genome-wide association studies on Crohn's disease. The results of these studies have implicated mutations in an essential autophagy gene, ATG16L1 (Hampe et al. 2007 Rioux et al. 2007). A significant association with Crohn's disease risk was found for patients bearing a variant of ATG16L1 expressing the coding SNP (T300A), and two recent studies discussed in detail elsewhere in this volume describe intestinal pathology in mice harboring mutations in Atg16L (see the chapter by Cadwell et al. in this volume). The importance of intestinal epithelial cells (IECs) in maintaining gut homeostasis is notable indeed, IECs must deal with a massive antigenic challenge from commensal bacteria and try to keep gut-associated lymphocytes in a state of immunological hyporesponsiveness. Since CD4+ T cells play a...

Blog Samonella Cerda

Abubakar I, Myhill D, Aliyu SH, Hunter PR (2008) Detection of Mycobacterium avium subspecies paratuberculosis from patients with Crohn's disease using nucleic acid-based techniques a systematic review and meta-analysis. Inflamm Bowel Dis 14 401-410 Alpuche-Aranda CM, Racoosin EL, Swanson JA, Miller SI (1994) Salmonella stimulate macrophage macropinocytosis and persist within spacious phagosomes. J Exp Med 179 601-608 Alvarez-Dominguez C, Roberts R, Stahl PD (1997) Internalized Listeria monocytogenes modulates intracellular trafficking and delays maturation of the phagosome. J Cell Sci 110 (Pt 6) 731-743 Amre DK, Mack DR, Morgan K, Krupoves A, Costea I, Lambrette P, Grimard G, Dong J, Feguery H, Bucionis V, Deslandres C, Levy E, Seidman EG (2009) Autophagy gene ATG16L1 but not IRGM is associated with Crohn's disease in Canadian children. Inflamm Bowel Dis 15 501-507 Baumgart M, Dogan B, Rishniw M, Weitzman G, Bosworth B, Yantiss R, Orsi RH, Wiedmann M, McDonough P, Kim SG, Berg D,...

Replication and Its Importance

A handful of susceptibility genes for common and complex diseases such as BRCA1 and BRCA2 in breast cancer (19,20), Calpain10 in NIDDM (21), NOD2 in Crohn's disease (22,23), Neuregulin 1 in schizophrenia (24), and ADAM33 in asthma (25) have been identified. Despite these successes, linkage studies of complex diseases have been difficult to replicate. A review of the linkage findings of 31 complex human diseases based on whole genome scan concluded

Systemic Inflammatory Disorders

Crohn's disease rarely involves the esophagus (110). Associated lesions include aphthous lesions, inflammatory strictures, fistulae, polyps, and large ulcers. Although these lesions may bleed acutely, there are no reported cases of acute upper GI bleeding attributed to Crohn's disease isolated to the esophagus, perhaps because of the exceedingly rare nature of this complication. Treatment with topical agents is often ineffective owing to the proximal distribution of the disease. Systemic immunomodulatory agents may be necessary to control Crohn's disease of the esophagus.

Human inflammatory bowel disease

Abnormalities of adipose tissue in the mesentery, including adipose tissue hypertrophy and fat wrapping, have been long recognized on surgical specimens as characteristic features of Crohn's disease. However, the importance, origin, and significance of the mesenteric fat hypertrophy in this chronic inflammatory disease are unknown. Desreumaux and colleagues evaluated this phenomenon and quantified intra-abdominal fat in patients with CD vs UC by using magnetic resonance imaging (51). By applying this technique they were able to demonstrate a significant accumulation of intraabdominal fat in patients with CD. This mesenteric obesity, present from the onset of disease, is associated with overexpression of PPARy as well as TNF-a mRNA, as evaluated by RT-PCR studies (51). In a subsequent study, the same group could demonstrate an overexpression of leptin mRNA in the mesenteric adipose tissue in inflammatory bowel disease, whereas no difference could be detected between UC and CD. The...

Alternative Indications For Dpp4 Inhibitors

Affect the function of other proteins that associate with CD26, specifically the PTPase activity of CD45 98 . Compound 45 is also known as talabostat or PT-100 and is in clinical trials for hematological malignancies and hematopoiesis 99 . The efficacy of 45 in these therapeutic indications may be derived from the compound's inhibition of FAP 100 . Numerous other reports have focused on the involvement of DPP4 and or use of DPP4 inhibitors in various inflammatory and autoimmune diseases and pathologies, such as Crohn's disease, 92 and organ transplantation 101 .

Interference with immune cell migration

Dramatically limits lymphocyte trafficking across the blood-brain barrier (Sheremata et al., 2005). Its beneficial effect in MS patients was shown in two Phase III clinical trials, both as a monotherapy (Polman et al., 2006) and as an add-on therapy to IFN-p-1a (Rudick et al., 2006). In both trials, Natalizumab treatment led to a substantial and significant decrease of relapse rate compared to placebo and a substantially lower proportion of disease progression, which corresponded to a dramatically reduced presence of lymphocytes in the CSF. However, two MS patients in the trials and one patient treated with Natalizumab in an independent study with Morbus Crohn developed progressive multifocal leukoencephalopathy (PML) during treatment (Kleinschmidt-DeMasters and Tyler, 2005 Langer-Gould et al., 2005 Van Assche et al., 2005). PML is caused by the reactivation and or de novo infection of oligodendrocytes with JC virus, which leads to a virus-induced progressive demyelination (Zurhein...

Emerging Opportunities for the Treatment of Inflammatory Bowel Disease

Introduction - Inflammatory Bowel Disease (IBD), in particular Crohn's disease (CD) and ulcerative colitis (UC), is a chronic and relapsing condition, characterised by an uncontrolled inflammatory response of the gastrointestinal tract. This leads to compromises in epithelial integrity, transmural inflammation, bleeding, diarrhoea and pain. However, in their clinical presentation, immunological bias (Th1 Th2) and genetic pre-disposition, CD and UC are distinct, requiring different medical and surgical management (1, 2). Whilst CD can present in any location between mouth and anus, UC is restricted to the large bowel, often initially confined to the most distal regions and advancing proximally. CD lesions are focal, penetrating the full thickness of the bowel and leading to perforation and fistulae, whereas UC lesions are generally more continuous and superficial in nature.

Physiological and pathological functions of PSGL1selectin interactions

The contributions of PSGL-1 to leukocyte adhesion in vivo have been documented in numerous studies, mostly in murine models. Studies with blocking mAbs to the N-terminal region of PSGL-1 initially demonstrated that PSGL-1 is the dominant ligand for mediating leukocyte rolling on P-selectin on inflamed endothelial cells in vivo 108, 109 (Fig. 2). Targeted disruption of the gene encoding murine PSGL-1 confirmed these observations very few PSGL-1-deficient leukocytes roll on P-selectin on activated venules, and those that do, roll very rapidly and irregularly 110, 111 . PSGL-1-deficient leukocytes exhibit reduced tethering to E-selectin in cytokine-activated venules however, those leukocytes that do tether to E-selectin roll with velocities equivalent to those of wild-type leukocytes 111 . Thus, PSGL-1 contributes to tethering to but not rolling on E-selectin, demonstrating that other E-selectin ligands are required for rolling (Fig. 2). One of the latter may be CD44 112 . Studies with...

Complications And Management

Enterocutaneous fistulas are more common in cases where small bowel has been resected for Crohn's disease or in cases where the small bowel has been previously irradiated. These fistulas are classified as high-, moderate-, or low-output depending on the volume over 24 h. High-output fistulas are those that put out more than 500 mL over 24 h (13). High-output fistulas are less likely to close with supportive measures. Low-

Alternatives And Costs

A review of the list of indications for small bowel resection (ischemia, tumor, Crohn's disease, Meckel's diverticulum) reveals a situation where nonsurgical options are few. At first glance, one would point out Crohn's disease as a disorder with multiple treatment options. In reality, however, Crohn's disease is a medical, not a surgical, problem. Patients require surgery because of complications associated with Crohn's disease (obstruction, abscess, bleeding, and so on) not on Crohn's disease per se. So, in fact, there are not any critical cost issues concerning surgery for disorders of small intestine.

Clinical Box 21 Graft Versus Host Disease

A main reason for the shortage of transplant organs is the fact that the tissues of the donor and the recipient need to match for successful transplantation. Tissues are matched when they have a similar pattern of cell surface proteins. Cell surface proteins are in fact glycoproteins due to the carbohydrates (sugars) attached to their surface. The carbohydrate acts as a flag designating the cell as belonging to the individual. The cellular gly-coprotein pattern may specify an individual within a species or specify a species. If a particular sugar is missing from the surface of a cell, the immune system may recognize this cell as foreign and try to kill it. An attack on self tissue may lead to autoimmune diseases, where the autoimmune reaction can be directed against a specific tissue such as the brain in multiple sclerosis or the digestive tube in Crohn disease. In other cases, the overly active immune system may attack many cells and tissues so that various organs are affected such...

Genital Ulcer Diseases

Most sexually transmitted genital ulcers in the UK are caused by Herpes simplex virus (HPA, 2005). Treponema pallidum is another common cause. Dark-ground microscopy, serological testing for syphilis and Herpes simplex culture can be performed to aid diagnosis. Nucleic acid amplification tests are also available for both organisms. Other sexually transmitted infective causes such as lymphogranuloma venereum, Haemophilus ducreyi and donovanosis should be considered, and a good travel history of both the patient and their partners is helpful. Other non-infective causes of genital ulcer disease include Behcet's disease and Crohn's disease.

Interactions of PSGL1 with other molecules

In vitro, the N terminus of PSGL-1 binds to some chemokines. Binding was shown to require tyrosine sulfation but not specific glycosylation of PSGL-1 125 . It remains possible that glycosylation could positively or negatively modulate che-mokine binding under some conditions. The ability of PSGL-1 to bind chemokines suggests new possibilities for how it could regulate leukocyte trafficking in vivo. For example, chemokines might transiently bind to PSGL-1 and then transfer to G protein-coupled chemokine receptors that activate leukocyte integrins. Binding of chemokines to PSGL-1 might explain why mAbs to the N terminus of PSGL-1 are more protective than a combination of mAbs to all three selectins in a murine model of Crohn's disease 17 .

Contraindications To Urinary Diversion

The patient with a history of inflammatory bowel disease poses a challenge to the surgeon in the selection of an appropriate bowel segment for diversion. Clearly, the use of the large bowel is to be avoided in the patient with ulcerative colitis. Likewise, the terminal ileum should not be used in patients with a history of Crohn's disease. This is particularly problematic because Crohn's disease may involve the entire gastrointestinal tract. In this situation, the use ofjejunum or stomach is preferable to the terminal ileum in the construction of the diversion. Ileal conduits are relatively contraindicated in children because of the risk of associated long-term chronic pyelonephritis and renal deterioration. Contraindications for orthotopic neobladder include tumor in the prostatic urethra, or in females, tumor at or near the bladder neck.

Lesions in the Small Intestine

The small bowel is the least frequent site of obscure GI bleeding, being the source in only 3-5 of patients. The most common sources of obscure bleeding from the small intestine are vascular malformations, reported in 8-40 of patients (12). Small bowel tumors are the second most frequent source of small bowel bleeding (13). Among patients with occult bleeding who are evaluated by push enteroscopy, vascular malformations are present in 0-6 (14). The findings with sonde enteroscopy report vascular malformations in 20-40 of patients and tumors in 0-8 (15). Less common sources of small intestinal bleeding are Crohn's disease, small bowel varices, diverticula, ulcers, Meckel's diverticulum, ischemia, celiac sprue, aortoenteric fistula, radiation enteritis, ulcerative jejunoileitis, blue rubber bleb nevus syndrome, Osler-Weber-Rendu syndrome, Dieulafoy's lesion, polyposis syndromes, amyloidosis, hemosuccus pancreaticus, and hemobilia. Treatment modalities are directed toward the underlying...

Conclusion and Clinical Perspectives

Interestingly, recent investigation of Nod family proteins, which may function as intracellular pattern-recognition sensors, has yielded information relevant to clinical diseases. In particular, mutation of Nod2 is thought to be associated with Crohn's disease (114,115), which, along with ulcerative colitis, are the prominent inflammatory bowel disorders. Nod2 acts as a signal modulator alongside TLR signals, and Nod2 mutation found in Crohn's disease results in enhanced NF-kB and cytokine signals (116-118). Further studies of Nod proteins will provide useful information that complements the investigation of TLR signal regulation outlined in this chapter. 114. Hugot, J. P., Chamaillard, M., Zouali, H., et al. (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599-603. 115. Ogura, Y., Bonen, D. K., Inohara, N., et al. (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603-606. 117....

Patients complaining of rectal bleeding consider

Blood separate from faeces is most commonly due to haemorrhoids, but may also be due to a variety of other causes, including rectal carcinoma and proctitis, which can be associated with a mucous discharge. Is the blood fresh - bright red, or old - darkish brown this can help indicate where the bleeding is from. When does the patient notice it A proctoscopy should be carried out, but it may be that further investigation may be needed outside of our realm of care, in which case refer appropriately. Blood mixed with faeces may be due to Crohn's disease, or inflammatory bowel disease, carcinoma or vascular abnormalities, and the patient should be referred for careful investigation via a gastroenterologist (Rhodes & Hsin, 1995).

Disorders of the Large Intestine and Rectum

Ulcerative colitis is a type of chronic inflammatory bowel disease. It is similar to Crohn's disease (see previous page), but it affects only the intestinal lining and is almost always restricted to the large intestine. Ulcerative colitis starts at the rectum and spreads upward through the large intestine. The disease causes chronic diarrhea that is usually bloody as the intestinal lining dies and sloughs off, ulcers form that release mucus, pus, and blood into the colon. Other symptoms include abdominal pain, fatigue, weight loss, loss of appetite, and rectal bleeding. The nonintestinal symptoms that can occur with Crohn's disease also can occur with ulcerative colitis. People whose ulcerative colitis extends throughout the entire colon are at much greater risk of developing colon cancer than are those whose disease is limited to the rectum and the sigmoid (lower) colon. Ulcerative colitis develops most frequently between ages 15 and 40. Most people with ulcerative colitis can...

Contraindications

Contraindications include the need for emergency surgery, Crohn's disease, the presence of invasive cancer, anal incontinence, morbid obesity, psychological instability, and advanced age. The operation is usually performed in two stages. At the first operation, a total colectomy is performed as described in the previous section, with rectal resection being carried down to approx 2-3 cm from the anal verge. In the past, the rectal mucosa was stripped from the remaining rectal stump, but, in general, this is no longer done. The rectum is divided with a stapler at that level and a reservoir pouch is then constructed from the distal 30 cm of terminal ileum. The most popular configuration of the pouch is a J shape, but S-shaped and W-shaped pouches have also been used. Following formation of the pouch, a circular stapled anastomosis is created between the apex of the pouch and a short rectal cuff. A proximal diverting ileostomy is then performed. The ileostomy is subsequently closed, as a...

Colostomy and Ileostomy

Treatment of Crohn's disease, ulcerative colitis, polyps, and colorectal cancer sometimes requires removal of all or part of the large intestine. Depending on how much tissue must be removed, the surgeon may need to create a new path for stool to pass from the body. Surgery to create a new opening (called a stoma) through the abdominal wall when the rectum is removed is called a colostomy if both the rectum and the colon must be removed, the procedure is known as an ileostomy.

What are genes What genes cause MS

Crohn's disease Mutations have occurred at a higher rate in the MHC region than in the rest of the human genome. Several mutations or alterations in this region that are more common in MS have been identified. These are sometimes referred to as polymorphisms. As you have undoubtedly heard the human genome project has deciphered our genetic code but many details regarding genes remain to be discovered. The human genome project is presently looking for a pattern of single nucleotide polymorphisms (SNPs pronounced as snips ) (i.e., a signature group of gene alterations in MS). Once an individual SNP is identified a search for the identity and function of the actual gene follows. A number of SNPs are anticipated to be associated with a predisposition to MS, as has been established for Crohn's disease, another autoimmune illness. Separately, in a recent Swedish study funded by the Montel Williams Foundation, the MHC2TA gene

Are there any medications that I should adjust or stop taking while Im being treated for osteoporosis

That has been used for years to manufacture estrogen, progesterone, and testosterone. Because DHEA is a precursor of testosterone, sometimes high dosages of it cause male characteristic side effects such as facial hair and acne, although doses around 50 mg or less do not appear to cause these side effects. DHEA has been touted as an anti-aging miracle drug. Its claimed effects include increased energy and better sex drive. Although DHEA is available over the counter, you must discuss its pros and cons with your clinician before trying it. The dosage of DHEA being used in clinical trials is about 150 mg to 200 mg per day. A clinical trial looking at DHEA's effect on Crohn's disease is also being conducted.

Small Bowel Imaging by Enteroclysis Enteroscopy or Given Capsule

Capsule endoscopy is a major recent advance that provides good visualization of the entire small intestine. Images are obtained by a capsule (13-mm diameter) that is swallowed and propelled by normal peristalsis within a few hours through the entire GI tract, with images taken many times per minute and sent by radio to a recording device that is worn on a harness around the patient's abdomen. The images can be reviewed at high speed after the study is completed. Angiodysplasias can be easily detected in a significant proportion of patients by capsule endoscopy. Although it is less invasive, a major limitation compared with intraoperative endoscopy is that capsule endoscopy does not allow any immediate therapeutic interventions. The Given capsule should not be used in patients suspected to have tight intestinal strictures (such as in some patients with Crohn's disease), because of the risk of obstruction. It is not very useful for evaluating the colon, because the capsule does not...

Data Interpretation

The pathogenesis of a number of diseases is still not very well understood. The exact mechanisms of containment of either transformed or virally infected cells have not been determined. In general, effective adaptive T-cell responses are desirable in these diseases. The flip side of the coin - in the context of cellular immune responses - is a strong T-cell response which mediates auto-immune disorders. Many parameters exist to measure disease activity in autoimmune diseases, but the magnitude of a cellular immune response is hard to assess, particularly if no molecular targets have been identified. Since TCR CDR3 analysis visualizes objectively every alteration in the TCR composition, it may be helpful to define new markers of disease activity in autoimmune diseases it may also present a potential matrix to gauge immuno-suppressive effects of novel drugs. For instance, TCR diversity has been suggested as a readout in PBL from patient suffering from SLE (39), or in the synovial fluid...

Are there treatments to prevent attacks and lessen risk of disability

Ized by 6 weeks of treatment and the accompanying reduction of sustained disability, the drug has been withdrawn from the market. The withdrawal was necessary because, unfortunately, 2 of the 589 patients who had received Avonex and Tysabri (one for 23 and the other for 37 months) developed PML, a fatal opportunistic viral disease of the brain. In addition, a patient with Crohn's disease who had received multiple drug therapies also developed this disease. Of the approximately 3,000 patients with MS, Crohn's disease, or rheumatoid arthritis, the only patients who developed PML were those two MS patients on combined Tysabri and Avonex therapy and the Crohn's disease patient who had received multiple immuno-suppressants as well as Tysabri. The drug has been withdrawn from the market pending a full review of the relevant facts.

The Mycobacterium avium Complex

MAC includes a variety of genetically related species with diverse pathogenic potential (10). M. avium subsp. avium (Maa) is common in the environment. It causes avian tuberculosis and sporadic infections of wild mammals (e.g., deer), as well as opportunistic infections in immunocompromised humans. M. avium subsp. silvaticum (Mas), the so-called wood pigeon bacillus, is primarily a bird pathogen. M. avium subsp.paratuberculosis (Map) causes Johne's disease and, although the hypothesis remains controversial, has been implicated as a cause of Crohn's Disease, a chronic inflammatory bowel disease in humans (73-75). MAC organisms exhibit greater heterogeneity than members of the M. tuberculosis complex. Multiple sequevars have been revealed by rDNA analysis and unidirectional deletion events cannot account for relationships between all isolates (9,76). Different branches appear to have acquired new genetic material via horizontal transfer (77). Genome comparison of Maa strain 104 (a human...

Therapeutic Antibodies

Several chimeric antibodies have received FDA approval and have been commercially successful in both the acute and chronic therapeutic setting. Two of the best known examples include Abciximab (ReoPro Centocor Eli Lill Fujisawa) and Infliximab (Remicade Centocor ScheringPlough Tanabe). Abciximab is an Fab fragment of a chimeric human-mouse monoclonal Ab that binds the glycoprotein llb llla and vitronectin receptors on human platelets and is indicated for acute blockade of platelet aggregation and subsequent thrombosis following percutaneous transluminal coronary angioplasty (14). Abciximab was approved in 1994. Infliximab (Remicade), approved in 1998, is a murine-human chimeric antibody that targets TNF-alpha (14). This antibody is indicated for chronic use in Crohn's disease and rheumatoid arthritis. Despite the reduction in murine content in these chimerized antibodies, HAMA responses have been reported to

Resuscitation Promoting Factors

J. (2003) Is Crohn's disease caused by a mycobacterium Comparisons with leprosy, tuberculosis, and Johne's disease. Lancet Infect. Dis. 3, 507-514. 75. Hermon-Taylor, J. and Bull, T. (2002) Crohn's disease caused by Mycobacterium avium subspecies paratuberculosis a public health tragedy whose resolution is long overdue. J. Med. Microbiol. 51, 3-6.

In Vivo Fluorescence Endomicroscopy in Inflammatory Bowel Disease

Inflammatory bowel diseases (IBD) comprise Crohn's disease and ulcerative colitis, which are defined as chronic inflammations of the gastrointestinal tract not due to specific pathogens 12 . Although the precise aetiology of inflammatory bowel disease remains unclear, augmented T-cell resistance to apoptosis is regarded as a pivotal factor in the pathogenesis 13 . While normal intestinal lamina propria T cells are highly susceptible to apoptosis, mucosal lymphocytes in Crohn's disease are less vulnerable to Fas-mediated apoptosis, which corresponds with an increased concentration of the anti-apoptotic protein Bcl-xl 14, 15 . Therefore novel therapeutic strategies aim at restoring intestinal T-cell susceptibility to apoptosis by targeting signal molecules that are pivotal for augmented apoptosis resistance in inflammatory bowel disease. The therapeutic rationale of the well-established treatment with chimeric anti-TNF-a monoclonal antibodies in IBD also seems to lie in rapid and...

Other Effects Of Thalidomide

In addition to its antiangiogenic activity, other effects of thalidomide have been reported. Thalidomide has been used in the treatment of lepromatous reaction (51-54), graft-versus-host disease (55-60), lupus erythematosis, Behcet's syndrome (61), rheumatoid arthritis (62,63), and Crohn's disease (64,65). Thalidomide has been shown to prolong graft survival in rat cardiac transplants (66,67) and to inhibit HIV replication (68). Macrophages appear to be a cellular target of thalidomide, since the drug has been shown to inhibit lipopolysaccharide-induced tumor necrosis factor-a production (69) by selective degradation of TNF-a mRNA (70), a pleiotropic cytokine that plays a central Amenorrhea is an interesting side effect of thalidomide (62,76) since in adults, the female reproductive cycle and wound healing (23) are dependent on angiogenesis. Indeed, this effect of thalidomide was exploited as a criteria for candidate antiangiogenic agents to be tested in the laboratory. Other effects...

Natalizumab Multiple Sclerosis [6874

The a4 family of integrins expressed on the surface of leukocytes are involved in cell adhesion processes. The a4 integrin can pair with either of two p subunits to generate a heterodimeric cell surface receptor known as a4pl (VLA4) or a4p7. Ligands for VLA4 include vascular cell adhesion molecule-l (VCAM-l), which is expressed on activated vascular endothelium, while a4p7 interacts predominantly with mucosal addressin cell adhesion molecule-l (MadCAM-l) existing on vascular endothelial cells of the gastrointestinal tract. By virtue of this a4-mediated interaction between leukocytes and vascular endothelial cells that leads to trans-end-othelial infiltration of various leukocytes (lymphocytes, monocytes, T-cells, etc.) at the site of inflammation, interference with the adhesion of the a4 integrin has been deemed a viable approach for disrupting the inflammatory cascade. As an antibody that binds to the a4 integrin subunit, natalizumab has been developed and launched for the treatment...

Clinical Presentation

In IBD, symptoms are usually chronic, although bloody diarrhea may bring the patient to a physician's attention. Bloody diarrhea is a predominant symptom in approximately 10-46 of patients with Crohn's disease (3), but most patients with ulcerative colitis have bloody diarrhea. Acute life-threatening lower GI bleeding is reported in 6-10 of those emergency surgical resections for ulcerative colitis but in only in 0.6-2 for Crohn's disease (4,5). As part of the history, it is helpful to know whether the patient has a family history of IBD, as well as smoking status. Patients who recently quit smoking are at higher risk for increased disease activity in ulcerative colitis patients with Crohn's disease tend to be smokers more often than the normal population (6). Ulcerative colitis typically begins in the rectum and extends proxi-mally. Symptoms tend to develop gradually, with the predominant symptom of diarrhea, accompanied by blood. Occasionally it may begin with infrequent stools but...

Beckwith Wiedemann Syndrome

Origin effects have also been attributed to various disorders including Crohn disease, epilepsy, and spina bifida. In addition, changes of imprinting patterns have been observed in different types of tumor cells. In some cancers demethy-lation activates a normally silenced gene (loss of imprinting, LOI), and in others methylation inactivates an expressed gene (gain of imprinting, GOI). Other kinds of changes to imprinted genes occur in tumor cells, such as the reversal of chromatin conformation from compacted (inactivation) to open (expression) or the reverse.

Sinus Tract and Fistulas

Because the organ that has the abnormal communication to the skin surface often has its own profuse indigenous flora. Examples are perirectal fistulas from the small bowel to the skin in association with Crohn's disease or chronic intraabdominal infection. When the bowel is involved, only cultures for specific key organisms, such as mycobacteria or Actinomyces, are meaningful. Always attempt to rule out specific underlying causes such as tuberculosis, actinomycosis, and malignancy. Biopsy should be performed in such situations.

Other Causes

Gastrinoma (Zollinger-Ellison syndrome), infections such as syphilis and tuberculosis, opportunistic infections such as cytomegalovirus and herpes simplex virus in immunosuppressed patients, and Crohn's disease are rare causes of ulcers in the upper GI tract. Neoplasm must be considered in the appropriate patient with gastric ulcer. True idiopathic ulcers also occur. Some such lesions are thought to be heredi

Future perspective

Based on this potent involvement of adipose tissue in immunity and the observation that preadipocytes can convert into macrophage-like cells that are capable of phagocytosing antigens (60), our current studies focus on whether adipocytes and their precursors are capable of directly interacting with pathogens. Preliminary data from these studies indicate that adipocytes as well as preadipocytes can be considered as new members of the innate immune system, as they not only express a variety of pattern recognition receptors but, in addition, can also functionally respond to receptor specific stimulation (Batra et al., unpublished data). This observation might be of particular interest because a recent study has confirmed a long-known concept indicating that the mesenteric adipose tissue of patients with Crohn's disease is colonized by bacterial flora, previously described as bacterial translocation (61). Thus the further characterization of the biological...

Caroline M Pond

Interactions between adipose and lymphoid tissues at the molecular, cellular, and tissue levels are summarized, with emphasis on the special composition and metabolic properties of perinodal adipose tissue that is anatomically associated with lymph nodes. Perinodal adipose tissue intervenes between the diet and nutrition of the immune system, modulating the action of dietary lipids on immune function. The roles of peptide- and lipid-derived messenger molecules are complementary precursors of prostaglandins and leukotrienes are specific fatty acids that are often essential constituents of the diet and may be supplied to lymphoid cells by paracrine interactions with adjacent adipocytes. Prolonged stimulation of paracrine interactions may induce local hypertrophy of adipose depots associated with lymphoid structures. Specialization of adipose tissue for paracrine interactions may be a unique, advanced feature of mammals that supports faster, more efficient immune processes and permits...

Abdominal

This is a chronic, localized, inflammatory process that often occurs weeks, months, or years after the integrity of the gastrointestinal mucosa is broken by surgery for acute appendicitis with perforation, or for perforated colonic diverticulitis, or by emergency surgery on the lower intestinal tract after trauma. Occasionally, abdominal actinomycosis may manifest without identifiable predisposing factors. The ileocecal region is involved most frequently (usually following appendicitis with perforation), with the formation of a mass lesion. The infection extends slowly to contiguous organs, especially the liver, and may involve retroperitoneal tissues, the spine, or the abdominal wall. Hepatic, renal, and splenic disseminations are uncommon complications (5). Persistent draining sinuses may form, and those involving the perianal region can simulate Crohn's disease or tuberculosis. The extensive fibrosis of actinomycotic lesions, presenting to the examiner as a mass, often suggests...

Vasculature

Lymphatic vessels are very small in the mucosal layer and somewhat difficult to identify. In chronic inflammatory bowel conditions such as Crohn's disease, the lymphatic vessels in the mucosa become visible due to the surrounding scarring and the subsequent dilatation of these vessels. In normal mucosa, most of the lymphatic vessels are collapsed and thus not readily identifiable.

Diagnosis

Ulcerative colitis may appear as mucosal edema, erythema with a loss of the vascular pattern, ulcerations, granularity, friability, spontaneous bleeding, mucopus, and mucosal detachment in a continuous pattern. Crohn's disease often spares the rectum and has skip areas. It classically appears as scattered apthous ulcers in mild disease or discrete, deep, longitudinal (bear claw) ulcers with interspersed normal mucosa in more severe disease. The presence of pseudopolyps or the loss of normal haustral folds suggests chronic inflammation.

Liver Abscess

Anaerobes may be involved in at least half of cases of pyogenic liver abscess (5). The most prevalent anaerobes in liver abscess are anaerobic and microaerophilic streptococci (not true anaerobes), Fusobacterium spp., B. fragilis group, and pigmented Prevotella and Porphyromonas spp. A colonic source is usually the initial source of infection. Staphylococcus aureus abscesses usually result from hematogenous spread of organisms involved with distant infections, such as endocarditis. Streptococcus milleri has been associated with both monomicrobial and polymicrobial abscesses in patients with Crohn's disease. S. aureus and beta-hemolytic streptococci are also associated with trauma Enterococcus spp., K. pneumoniae, and Clostridium spp. with biliary disease and Bacteroides and Clostridium spp. with colonic disease (Table 1).

Medical Therapy

For patients found to have inflammatory bowel disease, medical options are dependent on the type (Crohn's disease or ulcerative colitis), the extent, and the severity of disease. Table 3 outlines medical options for treating both ulcerative colitis and inflammatory Crohn's disease. For patients with suspected IBD who require hospi-talization, consultation with both a gastroenterologist and surgeon are appropriate (11). Hospitalize with surgical consultation Intravenous steroids (hydrocortisone or methylprednisolone) Cyclosporine Crohn's disease (inflammatory vs. fistulizing disease) Mild to moderate disease

Surgical Indications

Patients with Crohn's disease may have continued bleeding from aggressive transmural disease. If the patient continues to bleed after 24 hours of intravenous steroids and supportive care, further imaging is necessary to locate the source of bleeding. Because Crohn's disease can occur throughout the GI tract, nucleotide imaging or angiography may be necessary to visualize the source. Embolization is not recommended in this setting, and surgical resection of the affected site with either diverting ostomy or primary anastomosis is indicated.

Future Directions

The efforts of the Human Genome Project to define the basic organization of the genome and its polymorphism content, together with advances in cost-efficient genome-wide genotyping technology and analysis, have laid the groundwork for the final deconstruction of the MS genome. The potential of gene identification in complex diseases was recently highlighted by the discovery of the Complement Factor H gene associated with age-related macular degeneration 65 . In another example, Duerr et al. 31 demonstrated an association between variants in the IL23R gene and Crohn disease. In both cases, genetic discoveries led to a major leap in the understanding of disease pathogenesis. Several genome-wide association studies are underway in MS, but there are three important lessons coming from the Crohn disease and macular degeneration studies. First, replication of association findings is essential to distinguish artifacts from genuine positive results. Second, attention to phenotypic specificity...

Colitis

Inflammatory Bowel Disease (Ulcerative Colitis or Crohn's Disease) Although some bleeding is a common manifestation of inflammatory bowel disease, acute major lower GI hemorrhage is relatively rare, representing only 0.1 of all admissions for ulcerative colitis and 1.2 for Crohn's disease in a 7-year series at the Mayo Clinic (40). Lesions are often seen on colonoscopy, but most of these cannot be treated endo-scopically. Surgery is required in less than half of cases during the initial hospitalization. Recurrent hemorrhage is not rare, and for these cases surgery may be the most appropriate treatment.

What is the futureI

The surprising new findings in Crohn's disease of a new genetic mutation in 80 of a subset of patients that provides a rational explanation for the illness seemed unlikely just a year ago. This is now is a reality however, no one really anticipates finding an MS gene. However, this new finding in Crohn's disease exemplifies now that good genetic and biological research can provide unanticipated new discoveries in medicine. Research is the key to the future in MS, as it is for all of the biological sciences and in medicine.

Rectal pain

Fissured, macular and ulcerating lesions should be biopsied. Paget's and Bowen's diseases can only be diagnosed via histology, and are malignant diseases. Fistulas and perianal abscesses are easy to diagnose on examination. A main problem with this manifestation is not to recognise the possibility of underlying Crohn's disease, especially with the presence of thickened purplish skin tags, and another failing can be to assess the full extent of the fistula inaccurately. Further investigation by a specialist is commonly needed (Rhodes & Hsin, 1995). Anal tags are normal skin variation, and though they do not cause any symptoms or require treatment, sometimes they may be a clue to an underlying condition. As has earlier been stated, tags can be associated with Crohn's disease these tags are usually thick with a purplish appearance. Anal tags can occur as the result of a thrombosed external pile or may form the marked end to a chronic anal fissure.

Short Bowel Syndrome

Thirty-five to forty percent of patients with SBS have been found to develop gallstones (10). Risk factors for the development of cholelithiasis in patients with SBS include small intestinal length less than 120 cm, absent ileocecal junction, long-term total parenteral nutrition (TPN), and Crohn's disease (10). Cholestasis secondary to the use of TPN contributes to the formation of gallstones, although the administration of cholecystokinin may help to prevent biliary stasis. In stool, oxalate usually binds to intraluminal calcium to form an insoluble complex and is excreted. With fat malabsorption, calcium binds to free fatty acids resulting in large amounts of unbound oxalate. The free oxalate is absorbed in the colon and is eventually concentrated in the kidney leading to stone formation. Patients with hyperoxaluria should be placed on a low-oxalate low-fat diet to decrease urinary oxalate (1). In addition, cholestyramine can be added to bind free intraluminal oxalate and...

Conclusions

M., Alexander, A., Irving, M. H., Grant, M. E., and Shuttleworth, C. A., Distribution of the matrix metalloproteinases stromelysin, gelatinase A and B, and collagenase in Crohn's disease and normal intestines. J. Clin. Path. 47, 113-116 (1994).

Myositis

Psoas abscess generally develops as a result of spread from an adjacent structure, either as an extension of intra-abdominal infection (appendicitis, diverticulitis, Crohn's disease), perinephric abscess, or infected retroperitoneal hematoma. It can also originate from vertebral tuberculosis or S. aureus osteomyelitis. Osteomyelitis of the ilium or septic arthritis of the sacroiliac joint can produce iliacis or psoas abscess.

Miscellaneous

Unusual agents and those that have not been cultured, such as the mycobacteria that may be associated with Crohn's disease and the bacterium associated with Whipple's disease, identified by molecular methods as a new agent, Trophyrema whipplei, are also candidates as etiologic agents of GI disease. Occasionally, stool cultures from patients with diarrheal disease yield heavy growth of organisms such as enterococci, Pseudomonas spp., or