Cross-talk between inducible nitric oxide synthase and cyclooxygenase in Helicobacter-pylori-induced gastritis.

Objectives: The present study examined the cross-talk between prostanoids and nitric oxide (NO) in human gastric biopsies during Helicobacter pylori infection. Subjects and Methods: A pool of 1 or 2 biopsies per patient (11 H. pylori positive and 9 H. pylori negative) were incubated in the medium with/without drugs, 1400W and NS-398, inhibitors of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2), respectively. Levels of NO and prostaglandin E2 (PGE2), predominant products of activity of NOS and COX enzymes, were measured in the medium whereas the expressions of iNOS and COX protein, examined by Western blotting, were measured in the biopsies. Results: The 11 patients with H. pylori infection showed a marked expression of COX-2 and iNOS proteins and high levels of PGE2 and NO, as a consequence of iNOS and COX-2 activation, while proteins were absent and the level of nitrite and PGE2 was low in the 9 noninfected patients. The COX-2 inhibitor decreased both NO and PGE2. The iNOS-specific inhibitor decreased NO but did not have any effect on the increase in gastric mucosal PGE2. Both inhibitors had no effect on the protein level of these two enzymes. Conclusions: The data showed that COX-2 inhibitor might modulate the iNOS pathway, suggesting that COX-2 activity and/or its products may be related to the functional activation of iNOS but not to the expression of iNOS protein

Effect of Acute Exercise on Plasma Nitric Oxide Level in Humans

Objective: Since nitric oxide (NO) plays an important role in regulating vascular tone and changes in the plasma concentration of the end product of NO (nitrite/nitrate) have been observed during exercise, we studied the influence of acute exercise on nitrite/nitrate plasma levels in a group of semiprofessional football players and in younger and older sedentary subjects. Methods: The subjects exercised for 10 min on a cycle ergometer and blood samples were obtained at rest and immediately after exercise. Plasma samples were analysed for nitrite/nitrate. Results: The acute physical exercise induced a significant increase in nitrite/nitrate plasma levels both in sedentary and in active subjects. No difference was evident between the younger and older subjects, both in the basal level and after exercise, indicating that the changes could not be due to age. The higher basal plasma level of nitrite/nitrate observed in the active subjects compared with sedentary groups indicates that the state of physical conditioning had an effect on resting NO concentration. Conclusion: It seems that either acute exercise, even for a short time, or training can induce an increase in circulating NO

Host defense pathways against fungi : the basis for vaccines and immunotherapy

Fungal vaccines have long been a goal in the fields of immunology and microbiology to counter the high mortality and morbidity rates owing to fungal diseases, particularly in immunocompromised patients. However, the design of effective vaccination formulations for durable protection to the different fungi has lagged behind due to the important differences among fungi and their biology and our limited understanding of the complex host–pathogen interactions and immune responses. Overcoming these challenges is expected to contribute to improved vaccination strategies aimed at personalized efficacy across distinct target patient populations. This likely requires the integration of multifaceted approaches encompassing advanced immunology, systems biology, immunogenetics, and bioinformatics in the fields of fungal and host biology and their reciprocal interactions.The studies were supported by the Specific Targeted Research Project “ALLFUN” (FP7-HEALTH-2009-260338) and the Fondazione per la Ricerca sulla Fibrosi Cistica (FFC#21/2010, with the contribution of Francesca Guadagnin, Coca Cola Light® Tribute to Fashion and Delegazione FFC di Belluno). Agostinho Carvalho and Cristina Cunha were financially supported by fellowships from Fundação para a Ciência e Tecnologia, Portugal (contracts SFRH/BPD/46292/2008 and SFRH/BD/65962/2009, respectively)

Immunogenetic profiling to predict risk of invasive fungal diseases : where are we now?

Invasive fungal diseases remain nowadays life-threatening conditions affecting multiple clinical settings. The onset of these diseases is dependent on numerous factors, of which the "immunocompromised" phenotype of the patients is the more often acknowledged. However, and despite comparable immune dysfunction, not all patients are ultimately susceptible to disease, suggesting that additional risk factors, likely of genetic nature, may also be important. In the last years, genetic variants in several immune-related genes have also been proposed as major determinants of the susceptibility pattern of high-risk patients to invasive fungal diseases. Altogether, these findings highlighted the crucial significance of the individual genetic make-up in defining susceptibility to infection, providing a compelling rationale for the introduction of the immunogenetic profile as a risk prediction measure that may ultimately help to guide clinicians in the use of prophylaxis and preemptive fungal therapy in high-risk patients.Ricerca sulla Fibrosi Cistica (Project number FFC#21/2010)Fundação para a Ciência e a Tecnologia (FCT) SFRH/BD/65962/2009, SFRH/BPD/46292/200

Jack of all trades: thymosin α1 and its pleiotropy

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Immunity and Tolerance to Fungi in Hematopoietic Transplantation: Principles and Perspectives

Resistance and tolerance are two complementary host defense mechanisms that increase fitness in response to low-virulence fungi. Resistance is meant to reduce pathogen burden during infection through innate and adaptive immune mechanisms, whereas tolerance mitigates the substantial cost of resistance to host fitness through a multitude of anti-inflammatory mechanisms, including immunological tolerance. In experimental fungal infections, both defense mechanisms are activated through the delicate equilibrium between Th1/Th17 cells, which provide antifungal resistance, and regulatory T cells limiting the consequences of the ensuing inflammatory pathology. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme in the tryptophan catabolism, plays a key role in induction of tolerance against fungi. Both hematopoietic and non-hematopoietic compartments contribute to the resistance/tolerance balance against Aspergillus fumigatus via the involvement of selected innate receptors converging on IDO. Several genetic polymorphisms in pattern recognition receptors influence resistance and tolerance to fungal infections in human hematopoietic transplantation. Thus, tolerance mechanisms may be exploited for novel diagnostics and therapeutics against fungal infections and diseases

Postgrafting administration of granulocyte colony-stimulating factor impairs functional immune recovery in recipients of human leukocyte antigen haplotype–mismatched hematopoietic transplants

AbstractIn human leukocyte antigen haplotype–mismatched transplantation, extensive T-cell depletion prevents graft-versus-host disease (GVHD) but delays immune recovery. Granulocyte colony-stimulating factor (G-CSF) is given to donors to mobilize stem cells and to recipients to ensure engraftment. Studies have shown that G-CSF promotes T-helper (Th)-2 immune deviation which, unlike Th1 responses, does not protect against intracellular pathogens and fungi. The effect of administration of G-CSF to recipients of mismatched hematopoietic transplants with respect to transplantation outcome and functional immune recovery was investigated. In 43 patients with acute leukemia who received G-CSF after transplantation, the engraftment rate was 95%. However, the patients had a long-lasting type 2 immune reactivity, ie, Th2-inducing dendritic cells not producing interleukin 12 (IL-12) and high frequencies of IL-4– and IL-10–producing CD4+ cells not expressing the IL-12 receptor β2 chain. Similar immune reactivity patterns were observed on exposure of donor cells to G-CSF. Elimination of postgrafting administration of G-CSF in a subsequent series of 36 patients with acute leukemia, while not adversely affecting engraftment rate (93%), resulted in the anticipated appearance of IL-12–producing dendritic cells (1-3 months after transplantation versus > 12 months in transplant recipients given G-CSF), of CD4+ cells of a mixed Th0/Th1 phenotype, and of antifungal T-cell reactivity in vitro. Moreover, CD4+ cell counts increased in significantly less time. Finally, elimination of G-CSF–mediated immune suppression did not significantly increase the incidence of GVHD (< 15%). Thus, this study found that administration of G-CSF to recipients of T-cell–depleted hematopoietic transplants was associated with abnormal antigen-presenting cell functions and T-cell reactivity. Elimination of postgrafting administration of G-CSF prevented immune dysregulation and accelerated functional immune recovery

Conversion gastrectomy for stage IV unresectable gastric cancer: a GIRCG retrospective cohort study

Background: The aim of this study is to report the experience with conversion surgery from six Gruppo Italiano Ricerca Cancro Gastrico (GIRCG) centers, focusing our analysis on factors affecting survival and the risk of recurrence. Methods: A retrospective, multicenter cohort study was performed in patients who had undergone conversion gastrectomy between 2005 and 2017. Data were extracted from a GIRCG database including all metastatic gastric cancer patients submitted to surgery. Only stage IV unresectable tumors/metastases which became resectable after chemotherapy were included in this analysis. Results: Forty-five resected M1 patients were included in the analysis. Reasons for being deemed unresectable at diagnosis were peritoneal involvement (PCI > 6) (n = 38, 84.4%), distant metastatic nodes (n = 3, 6.6%) and extensive liver involvement (n = 4, 8.8%). Median follow-up was 25 months (IQR 9-50). Median overall survival from surgery was 15 months and 1-, 3- and 5-year survivals were 57.2, 36.1 and 24%, respectively. Median progression-free survival was 12 months with 1- and 3-year survival of 46.4 and 33.9%, respectively. At cox regression analysis the only independent prognostic factor for OS was the presence of more than one type of metastasis (HR 4.41, 95% CI 1.72\u201311.3, p = 0.002). A positive microscopic resection margin was the only risk factor for recurrence (HR 5.72, 95% CI 1.04\u201331.4, p = 0.045). Conclusions: Unresectable stage IV GC patients could benefit from radical surgery after chemotherapy and achieve long survivals. The main prognostic factor for these patients was the presence of more than one type of extra-gastric metastatic involvement

Spectro-polarimetric observations of the CIZA J2242.8+5301 northern radio relic: no evidence of high-frequency steepening

Observations of radio relics at very high frequency (>10 GHz) can help to understand how particles age and are (re-)accelerated in galaxy cluster outskirts and how magnetic fields are amplified in these environments. In this work, we present new single-dish 18.6 GHz Sardinia Radio Telescope and 14.25 GHz Effelsberg observations of the well known northern radio relic of CIZA J2242.8+5301. We detected the relic which shows a length of $\sim$1.8 Mpc and a flux density equal to $\rm S_{14.25\,GHz}=(9.5\pm3.9)\,mJy$ and $\rm S_{18.6\,GHz}=(7.67\pm0.90)\,mJy$ at 14.25 GHz and 18.6 GHz respectively. The resulting best-fit model of the relic spectrum from 145 MHz to 18.6 GHz is a power-law spectrum with spectral index $\alpha=1.12\pm0.03$: no evidence of steepening has been found in the new data presented in this work. For the first time, polarisation properties have been derived at 18.6 GHz, revealing an averaged polarisation fraction of $\sim40\%$ and a magnetic field aligned with the 'filaments' or 'sheets' of the relic.Comment: 10 pages, 8 figure

The bone marrow represents an enrichment site of specific T lymphocytes against filamentous fungi

Bone marrow has already been described as an enrichment site for several antigen-specific T lymphocytes, but the presence of mould-specific T cells has never been investigated in the bone marrow. We have previously demonstrated that mould-specific T cells emerge in the peripheral blood of patients with invasive fungal infections (IFI) but tend to become undetectable after disease resolution. In seven patients with a history of IFI, we investigated the presence of mould-specific T cells secreting different cytokines in bone marrow and peripheral blood paired samples. The results showed that the frequencies of mould-specific T cells secreting the protective cytokine IFNI3 are significantly higher in bone marrow (BM) and are mainly represented by CD8+ T lymphocytes with effector phenotype. A putative disappearance of such protective BM responses after myeloablative therapy could contribute to the increased risk of IFI in hematologic patients