Search

In the recent years, the incidence of inflammatory bowel disease (IBD) has dramatically increased in young subjects, however, the pathogenesis of paediatric IBD is poorly investigated. In this study we aimed to evaluate the cytokine pattern and the phenotype of cytokine producing cells in the intestinal mucosa of paediatric patients affected by Crohn's disease (CD) or ulcerative colitis (UC) and of non-IBD healthy controls (HC). Cytokine (IL-15, TNF-α, INF-γ) production was analyzed at basal condition and after mitogen stimulation either intracellularly by flow cytometry or in intestinal cell culture supernatants by enzyme-linked immunosorbent assay (ELISA). A higher frequency of enterocytes (EpCam+ cells) was observed in UC patients compared to CD or HC. An expansion of enterocytes producing IL-15 and TNF-α were found in IBD patients compared to HC. A marked expression of IL-15 in the intestinal epithelium of IBD patients was further confirmed by immunohistochemistry. Myeloid dendritic (CD11c+) cells producing TNF-α and INF-γ were increased in IBD biopsies. Unexpectedly, only after a strong mitogen stimulus, as phytohaemagglutinin, the frequency of CD3+ cells producing IFN-γ was increased in IBD compared to control intestinal mucosa. Interestingly, functional studies performed on organ cultures of intestinal biopsies with neutralizing anti-IL-15 monoclonal antibody showed a marked reduction of mononuclear cell activation, proliferation of crypt enterocytes, as well as a reduction of TNF-α release in organ culture supernatants. In conclusion, we found that in the gut mucosa of IBD children both enterocytes and dendritic cells produce proinflammatory cytokines. The over-expression of IL-15 by enterocytes in IBD intestine and the reduced IBD inflammation by IL-15 blockage suggests that this cytokine could be a therapeutic target in IBD.

Background: The objective of this study was to verify the association between the thoracic mortality and morbidity (TMM) classification system and hospital costs after lung resection., Methods: Consecutive patients (n = 503) submitted to anatomic lung resections were analyzed (April 1, 2014, to March 31, 2016). TMM system was used to grade the severity of complications. Postoperative costs were retrieved from the financial department using an electronic patient-level information system., Results: Two hundred seventy-two patients (54%) did not experience any complication. The distribution of postoperative complications in the remaining patients according to the TMM classification system was as follows: 57 (25%) grade I, 108 (47%) grade II, 29 (12%) grade III, 17 (7%) grade IV, and 20 (9%) grade V. The average postoperative cost of the uncomplicated patients was $3,560 (95% confidence interval [CI]: $3,440 to $3,680). The average postoperative costs of the patients with complications increased along with the grade of the TMM system; it was $4,548 (95% CI: $4,134 to $4,962) for grade I, $4,909 (95% CI: $4,537 to $5,281) for grade II, $6,392 (95% CI: $5,303 to $7,483) for grade III, and $14,547 (95% CI: $6,334 to $22,760) for grade IV. The average postoperative cost for the patients who eventually died was $17,695 (95% CI: $11,246 to $24,144). Linear regression analysis showed that a prolonged length of hospital stay (p < 0.0001) and an unplanned admission to the intensive care unit (p < 0.0001) were significantly associated with postoperative costs in patients with major complications., Conclusions: The severity of complications graded by the TMM system was associated with increasing postoperative costs. This instrument may be used to adjust lung resection reimbursement tariffs., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: To detect factors associated with costs of anatomic lung resection without major complications., Methods: Two hundred and fifty consecutive patients submitted to anatomic lung resection (185 by VATS) in 1 fiscal year (1 April 2014–31 March 2015) were included. Thoracic Morbidity and Mortality (TMM) system was used to grade the severity of complications. Two hundred and ten patients who did not develop major complications (TMM < 3) were analysed. Postoperative costs were retrieved from the Financial Department through a Patient Level Information and Costing System. Multivariable regression and bootstrap analyses were used to test the association of several baseline patient characteristics with costs and obtain an aggregate scoring system to estimate postoperative costs., Results: Among the 210 patients, 117 (56%) did not develop any complication and 93 (44%) had minor complications. Their average postoperative cost was 4040€, significantly lower than the one observed in patients with major complications (13 156€, P < 0.0001). Multivariable regression revealed that open thoracotomy (P = 0.01), carbon monoxide lung diffusion capacity (DLCO) < 60% (P = 0.001) and coronary artery disease (CAD) (P = 0.009) were associated with postoperative costs. Open thoracotomy would increase the cost by 648€, DLCO < 60% by 935€ and CAD by 1043€. If all three factors were present, they would cause an increase of postoperative costs from 3592€ to 6219€., Conclusion: We were able to identify clinical factors associated with postoperative costs in patients without major complications. Recognizing groups of increased cost may lead to specific process analyses aimed at optimising their pathways of care and ultimately saving money. Moreover, these findings may help administrators to tailor future individualized lung resection reimbursement tariffs based on patient characteristics., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Everolimus, an oral mTOR (mammalian target of rapamycin) inhibitor, is currently approved for the treatment of progressive pancreatic neuroendocrine tumors (NETs). Although promising, only scattered data, often from nondedicated studies, are available for extrapancreatic NETs., Patients and Methods: A systematic review of the published data was performed concerning the use of everolimus in extrapancreatic NET, with the aim of summarizing the current knowledge on its efficacy and tolerability. Moreover, the usefulness of everolimus was evaluated according to the different sites of the primary., Results: The present study included 22 different publications, including 874 patients and 456 extrapancreatic NETs treated with everolimus. Nine different primary sites of extrapancreatic NETs were found. The median progression-free survival ranged from 12.0 to 29.9 months. The median time to progression was not reached in a phase II prospective study, and the interval to progression ranged from 12 to 36 months in 5 clinical cases. Objective responses were observed in 7 prospective studies, 2 retrospective studies, and 2 case reports. Stabilization of the disease was obtained in a high rate of patients, ranging from 67.4% to 100%. The toxicity of everolimus in extrapancreatic NETs is consistent with the known safety profile of the drug. Most adverse events were either grade 1 or 2 and easy manageable with a dose reduction or temporary interruption and only rarely requiring discontinuation., Conclusion: Treatment with everolimus in patients with extrapancreatic NETs appears to be a promising strategy that is safe and well tolerated. The use of this emerging opportunity needs to be validated with clinical trials specifically designed on this topic., Implications for Practice: The present study reviewed all the available published data concerning the use of everolimus in 456 extrapancreatic neuroendocrine tumors (NETs) and summarized the current knowledge on the efficacy and safety of this drug, not yet approved except for pancreatic NETs. The progression-free survival rates and some objective responses seem promising and support the extension of the use of this drug. The site-by-site analysis seems to suggest that some subtypes of NETs, such as colorectal, could be more sensitive to everolimus than other primary NETs. No severe adverse events were usually reported and discontinuation was rarely required; thus, everolimus should be considered a valid therapeutic option for extrapancreatic NETs., (©AlphaMed Press.)

HLA genes represent the main risk factor in autoimmune disorders. In celiac disease (CD), the great majority of patients carry the HLA DQA1*05 and DQB1*02 alleles, both of which encode the DQ2.5 molecule. The formation of complexes between DQ2.5 and gluten peptides on antigen-presenting cells (APCs) is necessary to activate pathogenic CD4(+) T lymphocytes. It is widely accepted that the DQ2.5 genes establish the different intensities of anti-gluten immunity, depending whether they are in a homozygous or a heterozygous configuration. Here, we demonstrated that HLA DQA1*05 and DQB1*02 gene expression is much higher than expression of non-CD-associated genes. This influences the protein levels and causes a comparable cell surface exposure of DQ2.5 heterodimers between DQ2.5 homozygous and heterozygous celiac patients. As a consequence, the magnitude of the anti-gluten CD4(+) T cell response is strictly dependent on the antigen dose and not on the DQ2.5 gene configuration of APCs. Furthermore, our findings support the concept that the expression of DQ2.5 genes is an important risk factor in celiac disease. The preferential expression of DQ2.5 alleles provides a new functional explanation of why these genes are so frequently associated with celiac disease and with other autoimmune disorders., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aim: To investigate the correlation between autoimmune thyroid diseases (ATDs) and the prevalence of Cag-A positive strains of Helicobacter pylori (H. pylori) in stool samples., Methods: Authors investigated 112 consecutive Caucasian patients (48 females and 4 males with Graves' disease and 54 females and 6 males with Hashimoto's thyroiditis HT), at their first diagnosis of ATDs. Authors tested for H. pylori in stool samples using an amplified enzyme immunoassay and Cag-A in serum samples using an enzyme-linked immunoassay method (ELISA). The results were analyzed using the two-sided Fisher's exact test and the respective odds ratio (OR) was calculated., Results: A marked correlation was found between the presence of H. pylori (P ≤ 0.0001, OR 6.3) and, in particular, Cag-A positive strains (P ≤ 0.005, OR 5.3) in Graves' disease, but not in Hashimoto's thyroiditis, where authors found only a correlation with Cag-A strains (P ≤ 0.005, OR 8.73) but not when H. pylori was present., Conclusion: The marked correlation between H. pylori and Cag-A, found in ATDs, could be dependent on the different expression of adhesion molecules in the gastric mucosa.

Background: Viral and bacterial antigens have been suspected to be able to mimic the antigenic profile of the thyroid cell membrane and to play an important role in the onset of the autoimmune diseases, such as Graves' disease and Hashimoto thyroiditis. The Helicobacter pylori infection is worldwide diffused and is present in the developed countries up to 50% of the population. The presence of the cytotoxin-associated gene A antigens identifies the most virulent strains of the bacterium. Previous studies have demonstrated the possible correlation between the Helicobacter pylori and Hashimoto's thyroiditis but these results are controversial., Aims: We studied the prevalence rate of this bacterium in the Graves' disease and two selected subgroups such as the hyperthyroid patients, at the first time of diagnosis, and the euthyroid methimazole-treated patients., Materials and Methods: We analyzed Helicobacter pylori in fresh stool samples with an enzyme immunoassay method and the presence of cytotoxin-associated gene A antigens with a serological test., Results: Our results show that a significative increased rate of prevalence is present in Graves' patients, when the disease is ongoing, with an overall prevalence of the strains expressing the cytotoxin-associated gene A antigens compared to the control group., Conclusions: The association between the Helicobacter pylori and Graves' disease suggests a possible role of this bacterium in the onset and/or the maintenance of the disease., (© 2010 Blackwell Publishing Ltd.)

The expression of the beta 1 family of integrins was studied in normal thyroid tissue cultures and monolayer cell cultures. The expression of the various subunits was measured by flow cytofluorometry with specific monoclonal antibodies and by Northern analysis. In monolayer cell cultures but not in tissue cultures, the expression of the alpha 3 subunit on the cell membrane progressively increased soon after plating, reaching a 30-fold higher intensity. The alpha 2 subunit, not detectable in native follicular cells, was expressed de novo and reached a remarkable high level. Up-regulation of alpha 2 and alpha 3 in monolayer cell cultures was serum-independent and preceded the expression of proliferating cell nuclear antigen, [3H]thymidine incorporation, and cell replication. Northern analysis demonstrated an increased level of beta 1 integrin mRNA. The increase of alpha 2 and alpha 3 was readily reversible since the expression of these molecules returned to a lower level when cultures reached a high cell density. Down-regulation did not occur until cell cultures were confluent. When cells from high cell density and low integrin expression were harvested and sparsely seeded in culture, up-regulation of integrins was observed again, while rapid reaggregation of isolated cells inhibited this phenomenon. Altogether these data suggest that cell-to-cell contact may regulate the expression of beta 1 integrins in thyroid primary cultures.

The expression and cell-membrane distribution of the beta 1 family of integrins (very-late-activation antigens, VLA) were investigated in benign and malignant human thyroid tumors. We compared tissue samples of normal glands, nodular goiters, adenomas and carcinomas. We also examined 3 thyroid-carcinoma cell lines cultured in vitro. The expression of subunits of the beta 1 family of integrins was assessed by flow cytometry and specific antibodies in dispersed single-cell suspensions and by immunofluorescence on frozen tissue sections. In contrast to the heterogeneity of the expression of beta 1 integrins observed in other tumors, thyroid neoplastic lesions showed a remarkably constant VLA profile. In all tumors, benign as well as malignant, and in carcinoma cell lines, all sub-units of beta 1 integrins were expressed at high levels. While sub-units alpha 1, alpha 3, alpha 5, alpha 6 and occasionally alpha 2 were also present in a cell sub-set of normal glands and nodular goiters, expression of alpha 4 was restricted to neoplastic lesions; this integrin can be therefore considered an antigen associated with thyroid tumors. It has been reported that in normal glands and in nodular goiters, the expression of beta 1 integrins is restricted to the basal-cell membrane. Immunofluorescence on tissue sections showed instead that, in adenomas and carcinomas, the polarized distribution of these integrins on the cell membrane is lost.