Anti-nociceptive effect of Faecalibacterium prausnitzii in non-inflammatory IBS-like models

International audienceVisceral pain and intestinal dysbiosis are associated with Irritable Bowel Syndrome (IBS), a common functional gastrointestinal disorder without available efficient therapies. In this study, a decrease of Faecalibacterium prausnitzii presence has been observed in an IBS-like rodent model induced by a neonatal maternal separation (NMS) stress. Moreover, it was investigated whether F. prausnitzii may have an impact on colonic sensitivity. The A2-165 reference strain, but not its supernatant, significantly decreased colonic hypersensitivity induced by either NMS in mice or partial restraint stress in rats. This effect was associated with a reinforcement of intestinal epithelial barrier. Thus, F. prausnitzii exhibits anti-nociceptive properties, indicating its potential to treat abdominal pain in IBS patients

UN Peacekeeping at 75: Achievements, Challenges, and Prospects

This year marks the 75th anniversary of what the UN itself understands to be its first peacekeeping operation. It is therefore an appropriate time to reflect on the track record of UN peacekeeping in its efforts to try to maintain and realize peace and security. Moreover, this milestone invites us to ponder what lies ahead in the realm of peacekeeping. For this reason, this forum article brings together both academics and UN officials to assess the achievements and challenges of UN peacekeeping over the past 75 years. Through a dialogue among peacekeeping scholars and practitioners, we hope to identify current trends and developments in UN peacekeeping, as well as explore priorities for the future to improve the effectiveness of peacekeeping operations in terms of achieving their mandate objectives, such as maintaining peace, protecting civilians, promoting human rights, and facilitating reconciliation. This forum article is structured into six thematic sections, each shedding light on various aspects of UN peacekeeping: (1) foundational principles of UN peacekeeping - namely, consent, impartiality, and the (non-)use of force; (2) protection of civilians; (3) the primacy of politics; (4) early warning; (5) cooperation with regional organizations; and (6) the changing geopolitical landscape in which UN peacekeeping operates

Contextualising Support Models for African Peace operations

Lettere En WysbegeerteFilosofiePlease help us populate SUNScholar with the post print version of this article. It can be e-mailed to: [email protected]

Challenges, Key Issues and Future Directions

Lettere En WysbegeerteFilosofiePlease help us populate SUNScholar with the post print version of this article. It can be e-mailed to: [email protected]

Pigmentary traits, sun exposure, and risk of non-Hodgkin's lymphoma/chronic lymphocytic leukemia: A study within the French E3N prospective cohort.

To investigate whether risk factors for keratinocyte carcinomas (KCs), namely pigmentary traits and sun exposure, are associated with risk of non-Hodgkin's lymphomas (NHL) and chronic lymphocytic leukemia (CLL). E3N is a prospective cohort of French women aged 40-65 years at inclusion in 1990. Cancer data were collected at baseline and updated every 2-3 years. Hazard Ratios (HRs) and 95% confidence intervals (CIs) for associations between pigmentary traits and sun exposure, and risk of CLL/NHL were estimated using Cox models. With a median follow-up of 24 years, 622 incident cases of CLL/NHL were ascertained among the 92,097 included women. The presence of nevi was associated with CLL/NHL risk: HR for "many or very many nevi" relative to "no nevi": 1.56 [1.15; 2.11]. Such association with number of nevi appears to be mostly limited to risk of CLL: HR for "many or very many nevi": 3.00 [1.38; 6.52]; versus 1.32 [0.94; 1.84] for NHL. Women whose skin was highly sensitive to sunburn also had a higher risk of CLL: HR = 1.96 [1.21; 3.18], while no increase in risk of NHL was observed. Skin or hair color, number of freckles, and average daily ultraviolet (UV) dose during spring and summer in location of residence at birth or at inclusion (kJ/m2 ) were not associated with CLL/NHL risk. Some pigmentary traits (presence of nevi and skin sensitivity), but not sun exposure, were associated with CLL/NHL. These observations suggest that CLL may share some constitutional risk factors with keratinocyte cancers

Interactive involvement of brain derived neurotrophic factor, nerve growth factor, and calcitonin gene related peptide in colonic hypersensitivity in the rat

BACKGROUND AND AIMS: Neutrophins are involved in somatic and visceral hypersensitivity. The action of nerve growth factor (NGF) on sensory neurones contributes to the development of referred colonic hypersensitivity induced by trinitrobenzene sulfonic acid (TNBS). Based on data on brain derived neurotrophic factor (BDNF) and calcitonin gene related peptide (CGRP) in pain, the aims of the present study were: (1) to investigate the involvement of BDNF and CGRP in this model of referred colonic hypersensitivity, (2) to test the effect of exogenous BDNF and CGRP on the colonic pain threshold, and (3) to investigate the relationship between BDNF, NGF, and CGRP by testing antineurotrophin antibodies or h‐CGRP 8–37 (a CGRP antagonist) on bowel hypersensitivity induced by these peptides. METHODS: Colonic sensitivity was assessed using a colonic distension procedure. RESULTS: Anti‐BDNF antibody and h‐CGRP 8–37 reversed the induced decrease in colonic threshold (33.4 (2.1) and 40.3 (4.1) mm Hg, respectively, compared with a vehicle score of approximately 18 mm Hg; p<0.001). BDNF (1–100 ng/rat intraperitoneally) induced a significant dose dependent decrease in colonic reaction threshold in healthy rats. This effect was reversed by an anti‐BDNF antibody and an anti‐NGF antibody (33.4 (0.6) v 18.7 (0.7) mm Hg (p<0.001), anti‐NGF v vehicle). NGF induced colonic hypersensitivity was reversed by h‐CGRP 8–37 but not by the anti‐BDNF antibody. Finally, antineurotrophin antibody could not reverse CGRP induced colonic hypersensitivity (at a dose of 1 µg/kg intraperitoneally). CONCLUSION: Systemic BDNF, NGF, and CGRP can induce visceral hypersensitivity alone and interactively. This cascade might be involved in TNBS induced referred colonic hypersensitivity in which each of these peptides is involved

Widespread distribution of beta-hexosaminidase activity in the brain of a Sandhoff mouse model after coinjection of adenoviral vector and mannitol

Sandhoff disease is a severe inherited neurodegenerative disorder resulting from deficiency of the beta-subunit of hexosaminidases A and B, lysosomal hydrolases involved in the degradation of G(M2) ganglioside and related metabolites. Currently, there is no viable treatment for the disease. Here, we show that adenovirus-mediated transfer of the beta-subunit of beta-hexosaminidase restored Hex A and Hex B activity after infection of Sandhoff fibroblasts. Gene transfer following intracerebral injection in a murine model of Sandhoff disease resulted in near-normal level of enzymatic activity in the entire brain at the different doses tested. The addition of hyperosmotic concentrations of mannitol to the adenoviral vector resulted in an enhancement of vector diffusion in the injected hemisphere. Adenoviral-induced lesions were found in brains injected with a high dose of the vector, but were not detected in brains injected with 100-fold lower doses, even in the presence of mannitol. Our data underline the advantage of the adjunction of mannitol to low doses of the adenoviral vector, allowing a high and diffuse transduction efficiency without viral cytotoxicity

Colonic overexpression of the T‐type calcium channel Ca v 3.2 in a mouse model of visceral hypersensitivity and in irritable bowel syndrome patients

Abstract Background Among the different mechanisms involved in irritable bowel syndrome ( IBS ) physiopathology, visceral hypersensitivity seems to play a key role. It involves sensitization of the colonic primary afferent fibers, especially through an overexpression of ion channels. The aims of this translational study were to investigate the colonic expression of Ca v 3.2 calcium channels and their involvement in an animal model of colonic hypersensitivity, and to assess their expression in the colonic mucosa of symptomatic IBS patients. Methods This bench‐to‐bed study combined a preclinical experimental study on mice and a case–control clinical study. Preclinical studies were performed on wild‐type and Ca v 3.2‐ KO mice. Colonic sensitivity and Ca v 3.2 expression were studied after a low‐dose treatment of dextran sodium sulfate ( DSS 0.5%). Regarding the clinical study, colonic biopsies were performed in 14 IBS patients and 16 controls during a colonoscopy to analyze the mucosal Ca v 3.2 expression. Key results Wild‐type, but not Ca v 3.2‐ KO , mice developed visceral hypersensitivity without colonic inflammation, after 0.5% DSS treatment. A significant increase of Ca v 3.2 mRNA ( p = 0.04) was found in the colon of low‐dose DSS ‐treated wild‐type ( WT ) mice compared to their controls. In human colonic biopsies, the Ca v 3.2 mRNA level was significantly higher in the IBS group compared to the control group ( p = 0.01). The immunofluorescence staining revealed their protein expression in colonic mucosa, particularly in nerve fibers. Conclusions & inferences This translational study supports the involvement of the calcium channels Ca v 3.2 in abdominal pain, as observed in IBS patients. It opens new therapeutic perspectives based on molecules specifically blocking these channels