The pathophysiology of chagasic megacolon: beyond ICC…

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Influence of genetics on tumoral pathologies: The example of the adenocarcinoma arising in Barrett's esophagus

Barrett's esophagus (BE) refers to an abnormal change (metaplasia) in the cells of the inferior portion of the esophagus. About 10% of patients with symptomatic gastroesophageal reflux disease (GERD) have BE. In some cases, BE develops as an advanced stage of erosive esophagitis. The risk of esophageal cancer appears to be increased in patients with BE. The only way to diagnose BE is by endoscopy and histology. Some studies suggest that intensive treatment of Barrett's esophagus with effective acid suppression can reduce the amount of abnormal lining in the esophagus. It is not clear whether such treatment also prevents esophageal cancer. Generally, the cancer starts out as carcinoma of the esophagus on the surface, and then invades the surrounding tissue. Surgery offers the best chance of long-term survival. There are many events that occur in Barrett's esophagus that lead to the development of cancer and most of them appear to occur early, before high-grade dysplasia or cancer develops. No one knows what the late events are and how cells acquire the ability to leave their normal growth boundaries. It is now widely accepted that the development of most cancers is due to something called genomic or genetic instability. The aim of this review is to show BE pathology in its progression to cancer looking for new biomarkers to distinguish between BE-dysplasia (low grade and high grade)- adenocarcinoma (ADC) and to characterize the ADC, giving more hope for its treatment

Role of the Alteration in Calcium Homeostasis in Cell Death Induced by Clostridioides difficile Toxin A and Toxin B

Clostridioides difficile (C. difficile), responsible for 15–25% of gastrointestinal infections, causes health problems mainly due to the toxic activity of toxins A and B (Tcds). These are responsible for its clinical manifestations, including diarrhea, pseudomembranous colitis, toxic megacolon and death, with a mortality of 5–30% in primary infection, that increase following relapses. Studies on Tcd-induced cell death have highlighted a key role of caspases, calpains, and cathepsins, with involvement of mitochondria and reactive oxygen species (ROS) in a complex signaling pathway network. The complex response in the execution of various types of cell death (apoptosis, necrosis, pyroptosis and pyknosis) depends on the amount of Tcd, cell types, and Tcd receptors involved, and could have as initial/precocious event the alterations in calcium homeostasis. The entities, peculiarities and cell types involved in these alterations will decide the signaling pathways activated and cell death type. Calcium homeostasis alterations can be caused by calcium influx through calcium channel activation, transient intracellular calcium oscillations, and leakage of calcium from intracellular stores. These increases in cytoplasmic calcium have important effects on all calcium-regulated molecules, which may play a direct role in several cell death types and/or activate other cell death effectors, such as caspases, calpains, ROS and proapoptotic Bcl-2 family members. Furthermore, some support for the possible role of the calcium homeostasis alteration in Tcd-induced cell death originates from the similarity with cytotoxic effects that cause pore-forming toxins, based mainly on calcium influx through plasma membrane pores

Blue-green endoscopy in a dog presenting chronic vomiting-regurgitation

A 2-year-old male Maremma sheepdog presenting with chronic vomiting-regurgitation was examined at the University Veterinary Teaching Hospital, Camerino University. An oesophagogastroscopy with a single blue + green (BG) filter restricting wavelengths from 400 to 550 nm was carried out. A conventional white light endoscopy showed a dilated oesophagus with mildly diffuse erythematous mucosa (more accentuated proximal to the cardia); some portions of the gastric mucosa were covered with fluids and appeared only slightly erythematous. A blue green endoscopy highlighted the oesophageal lesions in dark blue, which made them appear more clearly defined from the remaining mucosa. In the gastric antrum, a small, slightly darker blue roundish area was visible. This area did not show up under the white light endoscopy. A histopathological assessment of biopsy specimens from the distal oesophagus, antrum (including the area highlighted only by BG endoscopy) and gastric body showed chronic-active hyperplastic esophagitis and superficial squamous epithelial dysplasia, while gastric samples showed severe diffuse hyperaemic gastritis of the antrum and superficial diffuse atrophy of the gastric body. The authors believe that the use of a BG endoscopy could be useful in veterinary medicine to increase the diagnostic potential of endoscopic assessment in animals

avoiding biopsy in iron deficiency anemia is not a cost effective approach

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Clostridioides difficile Infection in Patients with Inflammatory Bowel Disease May be Favoured by the Effects of Proinflammatory Cytokines on the Enteroglial Network

Clostridioides difficile infection is widespread throughout countries and represents an important cause of nosocomial diarrhoea, with relatively high morbidity. This infection often occurs in patients with inflammatory bowel diseases and may complicate their clinical picture. Here, we propose, on the basis of evidence from basic science studies, that in patients affected by inflammatory bowel diseases, this infection might be facilitated by a derangement of the enteric glial cell (EGC) network caused by the effects of proinflammatory cytokines, such as tumour necrosis factor alpha and interferon gamma, which enhance the cytotoxic effects of C. difficile toxin B on EGCs. This hypothesis, if confirmed, could open the door to alternative treatment approaches to fight C. difficile infection

Cytotoxic synergism of Clostridioides difficile toxin B with proinflammatory cytokines in subjects with inflammatory bowel diseases

Clostridioides difficile (C. difficile) is progressively colonizing humans and animals living with humans. During this process, hypervirulent strains and mutated toxin A and B of C. difficile (TcdA and TcdB) are originating and developing. While in healthy subjects colonization by C. difficile becomes a risk after the use of antibiotics that alter the microbiome, other categories of people are more susceptible to infection and at risk of relapse, such as those with inflammatory bowel disease (IBD). Recent in vitro studies suggest that this increased susceptibility could be due to the strong cytotoxic synergism between TcdB and proinflammatory cytokines the tumor necrosis factor-alpha and interferon-gamma (CKs). Therefore, in subjects with IBD the presence of an inflammatory state in the colon could be the driver that increases the susceptibility to C. difficile infection and its progression and relapses. TcdB is internalized in the cell via three receptors: chondroitin sulphate proteoglycan 4; poliovirus receptor-like 3; and Wnt receptor frizzled family. Chondroitin sulphate proteoglycan 4 and Wnt receptor frizzled family are involved in cell death by apoptosis or necrosis depending on the concentration of TcdB and cell types, while poliovirus receptor-like 3 induces only necrosis. It is possible that cytokines could also induce a greater expression of receptors for TcdB that are more involved in necrosis than in apoptosis. Therefore, in subjects with IBD there are the conditions: (1) For greater susceptibility to C. difficile infection, such as the inflammatory state, and abnormalities of the microbiome and of the immune system; (2) for the enhancement of the cytotoxic activity of TcdB +Cks; and (3) for a greater expression of TcdB receptors stimulated by cytokines that induce cell death by necrosis rather than apoptosis. The only therapeutic approach currently possible in IBD patients is monitoring of C. difficile colonization for interventions aimed at reducing tumor necrosis factor-alpha and interferon-gamma levels when the infection begins. The future perspective is to generate bacteriophages against C. difficile for targeted therapy

Proinflammatory Cytokines: Possible Accomplices for the Systemic Effects of Clostridioides difficile Toxin B

Clostridioides difficile infection (CDI) has a serious impact on the healthcare system, and most of its pathogenic effects are mainly due to the activity of toxins A and B (TcdA and TcdB, respectively). The molecular mechanisms of their cytotoxic activity are well known, especially in the colon, where the infection occurs and normally remains localized. However, the mechanisms causing toxic effects on various systemic organs (extraintestinal manifestations) with frequent lethal outcomes in some patients affected by CDI are still poorly understood. Few studies are available that demonstrate low serum levels of Tcds in both experimental animal models and patients with CDI. Until now, it has remained unclear how low levels of circulating Tcds could lead to serious toxic effects. On the basis of our previous in vitro studies, in which the proinflammatory cytokines TNFalpha and IFN-gamma strongly potentiated the toxic activity of low doses of TcdB, we hypothesize that the presence of both TcdB in the circulation and a systemic proinflammatory cytokine storm may be responsible for the selective severe effects of TcdB in some patients. This may occur in patients with severe CDI and systemic Tcds, in whom proinflammatory cytokines such as TNF-alpha and IFN-gamma reach a significant concentration in the circulation. This hypothesis could identify therapeutic interventions based on the reduction or neutralization of the indirect toxic action of these cytokines

Non-IBD colitides: clinically useful histopathological clues.

Apart from inflammatory bowel diseases (IBD), there are several other form of colitis that may resemble macroscopically IBD, entering the differential diagnosis. These forms are represented by infectious colitis, ischemic colitis, pseudomembranous colitis, colitis related to diverticular disease, colitis related to mucosal prolapse, drug colitis, allergic colitis, and microscopic colitis. However, to distinguish between these forms is not always easy, and it frequently requires a strict interrelationship between the pathologist and the gastroenterologist. Here we discuss the more frequent forms of non- inflammatory bowel diseases colitides, trying to give useful hints for helping the clinician to better understand the extent to which the pathologist is called to give a definitive response in the differential diagnosis of these entities