Javiera Torres

Helicobacter pylori gastritis in children is associated with a regulatory T-cell response.

BACKGROUND & AIMS Helicobacter pylori infection in children infrequently causes gastroduodenal mucosal ulceration. Because H pylori induces T-cell dependent gastric inflammation in adults and T regulatory (Treg) cells suppress T-cell-dependent pathology, we evaluated gastric histopathology and Treg cell responses in H pylori-infected children and adults. METHODS Gastric tissue from 36 children and 79 adults with abdominal symptoms in Santiago, Chile, was evaluated prospectively for H pylori bacteria and histopathology using the Sydney classification and Treg responses using immunoassay, immunohistochemistry, and real-time polymerase chain reaction. RESULTS Eighteen (50%) of the children and 51 (65%) of the adults were infected with H pylori. Children and adults were colonized with similar levels of H pylori. However, the level of gastritis in the children was reduced substantially compared with that of the adults (P < .05). Coincident with reduced gastric inflammation, the number of Treg cells and levels of Treg cytokines (transforming growth factor [TGF]-beta1 and interleukin-10) were increased markedly in the gastric mucosa of H pylori-infected children compared with that of infected adults (P < .03 and < .05, respectively). Also, H pylori infection in the children was associated with markedly increased levels of gastric TGF-beta1 and interleukin-10 messenger RNA. Importantly, gastric TGF-beta1 in H pylori-infected children localized predominantly to mucosal CD25(+) and Foxp3(+) cells, indicating a Treg source for the TGF-beta1. CONCLUSIONS Gastric pathology is reduced and local Treg cell responses are increased in H pylori-infected children compared with infected adults, suggesting that gastric Treg cell responses down-regulate the inflammation and ulceration induced by H pylori in children.

Interleukin-10 plays a key role in the modulation of neutrophils recruitment and lung inflammation during infection by Streptococcus pneumoniae.

Streptococcus pneumoniae is a major aetiological agent of pneumonia worldwide, as well as otitis media, sinusitis, meningitis and sepsis. Recent reports have suggested that inflammation of lungs due to S. pneumoniae infection promotes bacterial dissemination and severe disease. However, the contribution of anti‐inflammatory molecules to the pathogenesis of S. pneumoniae remains unknown. To elucidate whether the production of the anti‐inflammatory cytokine interleukin‐10 (IL‐10) is beneficial or detrimental for the host during pneumococcal pneumonia, we performed S. pneumoniae infections in mice lacking IL‐10 (IL‐10−/− mice). The IL‐10−/− mice showed increased mortality, higher expression of pro‐inflammatory cytokines, and an exacerbated recruitment of neutrophils into the lungs after S. pneumoniae infection. However, IL‐10−/− mice showed significantly lower bacterial loads in lungs, spleen, brain and blood, when compared with mice that produced this cytokine. Our results support the notion that production of IL‐10 during S. pneumoniae infection modulates the expression of pro‐inflammatory cytokines and the infiltration of neutrophils into the lungs. This feature of IL‐10 is important to avoid excessive inflammation of tissues and to improve host survival, even though bacterial dissemination is less efficient in the absence of this cytokine.

Altered Chemokine Receptor Expression in Papillary Thyroid Cancer

BACKGROUND Papillary thyroid cancer (PTC), the most prevalent type of differentiated thyroid carcinoma, displays a strikingly high frequency of lymph node metastasis (LNM). Recent data suggest that chemokines can play an important role in promoting tumor progression and metastatic migration of tumor cells. Here we have evaluated whether PTC tissues express a different pattern of chemokine receptors and if the expression of these receptors correlates with LNM. METHODS We assessed by immunohistochemistry and flow cytometry the expression of the chemokine receptors CCR3, CCR7, and CXCR4 in tumor and nonmalignant thyroid tissues from patients suffering from PTC. Expression of these receptors in PTC was correlated with the clinical pathological condition of PTC. RESULTS Our data show a significant enhancement of CCR3 (2.5 times higher, p = 0.038) and CXCR4 (1.7 times higher, p = 0.02) expression in PTC tissues as determined by immunohistochemical staining, and of CCR3 (3.5 times higher, p < 0.002) in the plasma membrane as determined by flow cytometric analyses, compared to controls. In addition, while CCR3 (100%) and CXCR4 (90%) were present in both tumor and control thyroid tissues, expression of CCR7 was scarcely detected in PTC cells (5-10%) and not found in control cells. CXCR4 expression correlated with the classical variant of PTC (p < 0.035) and extranodal extension (p < 0.010) in patients with LNM. CONCLUSIONS Our data support the notion that CCR3, CCR7, and CXCR4 are increasingly expressed in tumor cells from PTC and that CXCR4 expression in PTC could be a potential marker for enhanced tumor aggressiveness.

Overexpression of p73 as a Tissue Marker for High-Risk Gastritis

Purpose: Histologic assessment of high-risk gastritis for the development of gastric cancer is not well defined. The identification of tissue markers together with the integration of histologic features will be required for this assessment. Experimental Design: Matched tumor/nontumor adjacent mucosa (NTAM) of 91 early gastric cancer and 148 chronic gastritis cases were evaluated for histologic characteristics (atrophy, intestinal metaplasia, chronic inflammation, polymorphonuclear infiltration, and Helicobacter pylori) by the Sydney System. Atrophy risk assessment was also evaluated by the Operative Link on Gastritis Assessment (OLGA) staging system. Eight tissue markers (BRCA1, HSP90, STAT1, FHIT, EGFR, p73, p53, p16INK4a) and EBV were also evaluated by tissue microarray/immunohistochemistry/in situ hybridization platform. Data were analyzed by contingency tables (2 × 2) using Fishers exact two-tailed test (P < 0.001) and integrated by Significance Analysis of Microarrays (SAM) and clustering analysis. Results: Histologically, NTAM have severe intestinal metaplasia/chronic inflammation and severe atrophy assessed by Sydney and OLGA staging systems. H. pylori infection was similar in both groups, and EBV was found only in 5.5% of the tumor samples. Overexpression of p73 was higher in NTAM (50.5%) than in chronic gastritis (10.8%; P < 0.0001). Integration of histologic features and tissue markers showed that overexpression of p73, severe atrophy, and OLGA stage 4 were the most relevant features in NTAM. Clustering analysis correctly assigned NTAM and control cases (P < 0.0001). Conclusions: Overexpression of p73 should be considered for the assessment of high-risk chronic gastritis. SAM allows the integration of histology and tissue markers for this assessment. Clin Cancer Res; 16(12); 3253–9. ©2010 AACR.

Peptic ulcer disease in Helicobacter pylori-infected children: clinical findings and mucosal immune response.

Objectives: Peptic ulcer disease (PUD) is highly prevalent among adults but less common in children. Helicobacter pylori infection, the main cause of PUD, is, however, acquired extremely early in life. The aim of the study was to analyze clinical characteristics of children with PUD in a country with a high prevalence of the disease and to evaluate which host factors could determine this clinical outcome. Methods: Children referred for upper gastrointestinal (GI) endoscopy with suspicion of peptic diseases were included prospectively during an 8-year period. Antral biopsies were performed to determine H pylori presence and mucosal cytokines profile. Results: A total of 307 children between 3 and 18 years old were enrolled. Of the total, 237 children (46% boys) with complete data were included. H pylori infection was confirmed in 133 (56.1%) participants. Duodenal ulcer (DU) was diagnosed in 32 patients (13.5%); among them 29 were infected with H pylori (90.6%). Infected children had a nodular appearance of the gastric mucosa more often than noninfected children. Noninfected children had fewer lymphoid follicles and less inflammatory infiltrate than infected children. Only mucosal polymorphonuclear cell infiltration was more intense in DU-infected children as compared with non–DU-infected children. DU-infected children had higher levels of mucosal interferon-&ggr; than noninfected and non–DU-infected patients. Non–DU-infected children had also higher levels of mucosal interleukin-10 than noninfected patients (P < 0.05). Conclusions: PUD in children, especially DU, is strongly associated with H pylori infection in developing countries. There is no distinctive clinical presentation of children with PUD. T-helper cytokine balance may influence clinical outcomes in children.

Inverse correlation between allergy markers and Helicobacter pylori infection in children is associated with elevated levels of TGF-β.

Objectives We evaluated allergy/hypersensitivity clinical markers and their correlation with Helicobactor pylori infection in children and adults to analyze how early acquisition of H. pylori could modulate allergic disorder expression. Patients and methods H. pylori presence was assessed by the rapid urease test and histology of antrum biopsies in 165 patients. Skin tests, serum IgE, and two clinical allergy questionnaires were performed. Allergy severity was operationally defined using a combined score. Findings were correlated with H. pylori status and cytotoxin-associated gene A presence in pediatric and adult patients. Transforming growth factor &bgr; (TGF-&bgr;) levels were measured by an enzyme-linked immunosorbent assay in serum and gastric biopsies of H. pylori (+) patients. Results H. pylori (−) children had more positive skin tests to a higher number of antigens than H. pylori (+) children (P<0.05). Operationally defined allergy inversely correlates with H. pylori infection in children, but not in adults. The percentage of H. pylori infection was lower in children with severe allergy (32.3%) compared with children with mild allergy (43.4%) or no allergy (64.3%) (P<0.05). Colonization with virulent strains (cytotoxin-associated gene A+) showed a nonsignificant inverse correlation with severity of allergies in pediatric patients. H. pylori-infected children, but not adults, without allergy markers showed increased levels of TGF-&bgr; compared with allergic children both in serum and gastric mucosa (P<0.05). Conclusion There was a strong inverse correlation between allergy markers and H. pylori infection in pediatric patients associated with elevated levels of TGF-&bgr; locally and systemically. H. pylori-associated chronic gastritis might downregulate clinical allergy expression.

Andrographolide Ameliorates Inflammation and Fibrogenesis and Attenuates Inflammasome Activation in Experimental Non-Alcoholic Steatohepatitis

Therapy for nonalcoholic steatohepatitis (NASH) is limited. Andrographolide (ANDRO), a botanical compound, has a potent anti-inflammatory activity due to its ability to inhibit NF-κB. ANDRO has been also shown to inhibit the NLRP3 inflammasome, a relevant pathway in NASH. Our aim was to evaluate the effects of ANDRO in NASH and its influence on inflammasome activation in this setting. Thus, mice were fed a choline-deficient-amino-acid–defined (CDAA) diet with/without concomitant ANDRO administration (1 mg/kg, 3-times/week). Also, we assessed serum levels of alanine-aminotransferase (ALT), liver histology, hepatic triglyceride content (HTC) and hepatic expression of pro-inflammatory, pro-fibrotic and inflammasome genes. Inflammasome activation was also evaluated in fat-laden HepG2 cells. Our results showed that ANDRO administration decreased HTC and attenuated hepatic inflammation and fibrosis in CDAA-fed mice. ANDRO treatment determined a strong reduction in hepatic macrophage infiltration and reduced hepatic mRNA levels of both pro-inflammatory and pro-fibrotic genes. In addition, mice treated with ANDRO showed reduced expression of inflammasome genes. Finally, ANDRO inhibited LPS-induced interleukin-1β expression through NF-κB inhibition in fat-laden HepG2 cells and inflammasome disassembly. In conclusion, ANDRO administration reduces inflammation and fibrosis in experimental NASH. Inflammasome modulation by a NF-κB-dependent mechanism may be involved in the therapeutic effects of ANDRO.

Esofagitis eosinofílica en niños: Características clínicas y endoscópicas

Eosinophilic esophagitis in adults (EE) is a disease of unknowncause, characterized by symptoms such as reflux and dysphagia that traditionally do notrespond to antacid treatment. It affects mostly young men with a strong personal or familialhistory of atopy, asthma and allergies. We report three male patients aged 10, 14 and 15 years,all with symptoms of dysphagia, two of them with chest pain caused by spasm of the esophagus,with heterogeneous endoscopic findings which included from leucoplakia to stenosis thatneeded endoscopic dilatation. All of them had abnormal findings in immunity studies (pricktest or IgE levels). They received treatment based on diet measures, acid suppression andleukotriene inhibitors, with satisfactory clinical, endoscopic and histological response. EEshould be suspected in children and adults with esophageal symptoms and personal or familyhistory of allergy and asthma (Rev Med Chile 2009; 137: 666-71).(

Cervical metastases of glucagonoma in a patient with multiple endocrine neoplasia type 1: Report of a case

Multiple endocrine neoplasia type 1 (MEN 1) is a syndrome characterized by tumors of the parathyroid glands, pancreatic islet cells, duodenum, and pituitary gland. We report a case of cervical metastases of glucagonoma with MEN 1. The patient was a 34-year-old woman admitted to our hospital with epigastric pain. Her medical history included two resections of prolactinoma and two upper GI hemorrhages secondary to duodenal ulcers. Computed tomography (CT) showed two hypervascular lesions in the tail of the pancreas and cervical ultrasound showed multiple hypoechogenic ovoid images in the neck. A cervical CT scan confirmed two 15-mm lymph nodes in the left cervical region and 111In-DOTATOC imaging showed focal abnormal somatostatin expression in the pancreatic tail and the cervical nodes. The patient had asymptomatic hypoglycemic episodes, with blood sugar levels as low as 30 mg/dl, which raised our suspicion of MEN 1 associated with pancreatic insulinoma. Thus, we performed a distal pancreatectomy with bilateral cervical dissection and parathyroid gland resection. Histopathological examination revealed 12 pancreatic tumors as well as metastases in four cervical lymph nodes. The resected parathyroid glands had normal structure, suggesting parathyroid hyperplasia. A follow-up CT scan, 18 months after surgery, showed new tumors in the head of the pancreas and in the duodenal wall. A pancreatoduodenectomy was performed and histopathological examination revealed nine nonfunctioning endocrine tumors in the pancreas, one tumor in the duodenal wall, and metastases in two peripancreatic lymph nodes. The patient recovered well and remains asymptomatic.

Sobrevida alejada de pacientes operados por cáncer gástrico incipiente

BACKGROUND Early gastric cancer involves mucosa and submucosa, independent of lymph node involvement. Radical gastrectomy is the standard treatment. AIM To assess long term survival of patients operated for an early gastric cancer. MATERIAL AND METHODS Retrospective review of medical and pathology records of patients subjected to a gastrectomy for an early gastric cancer, between 1975 and 2002. All were treated using a standardized protocol and staged according to 2002 TNM classification of the American Joint Committee of Cancer (AJCC). Demographic and pathologic features, operation performed and long term survival were recorded. Survival was analyzed using Kaplan-Meier method. RESULTS The series is comprised by 64 males and 41 females aged 61 +/- 1 years. Tumor was located in the upper third of the stomach on 33 subjects and a total gastrectomy was performed in 53. Pathology showed an intestinal type adenocarcinoma in 82 and a diffuse type in 23. In patients with involvement of mucosa and submucosa, 24 +/- 14 and 22 +/- 14 lymph nodes were excised, respectively. Lymph node involvement was present in 8% and 22% of patients with involvement of mucosa and submucosa, respectively. Five years survival was 94% and 78% in patients without and with lymph node involvement, respectively. Survival among patients in stage IA and IB was 94% and 76%, respectively. Multivariate analysis showed that the lymph node involvement was an independent mortality risk factor. CONCLUSIONS Total gastrectomy in patients with early gastric cancer is associated with a good survival. Lymph node involvement is a mortality risk factor.