Increase in circulating microparticles in inflammatory bowel disease patients induces vascular alterations

Alterations of vascular function participate to the development of the inflammatory bowel disease (IBD). We have previously reported the presence of inflammation-related vasoactive factors in small mesenteric arteries from Crohn’s disease patients (Tabernero et al., Circulation, 2003). Microparticles (MPs) are membrane vesicles released during cell activation and apoptosis whose circulating levels have been shown to be increased in patients with IBD, including MPs from platelets and activated platelets, endothelial, leukocyte and erythrocyte origins (Leonetti et al., Archives of Cardiovascular Diseases, Tome 102-Supplement 1-Mars 2009.).Here, we investigated whether MPs from IBD patients (IBD-MPs) play a role in the regulation of endothelial function and vascular reactivity in this disease. Male Swiss mice were injected intravenously with IBD-MPs or saline solution and sacrificed 24 h after. Endothelial function and vascular reactivity were studied on aortic rings by myography. The involvement of nitric oxide (NO), cyclooxygenase (COX) metabolites and superoxide anion (O2- ) was also assessed using the following inhibitors: NG-L-Nitro-arginine (NO synthase inhibitor, L-NA); indomethacin (non-selective COX inhibitor); SC-560 (selective COX-1 inhibitor), NS-398 (selective COX-2 inhibitor) and MnTMPyP (permeable superoxide dismutase mimetic). In aorta, IBD-MPs significantly reduced both endothelium-dependent induced by acetylcholine and the NO donor, sodium nitroprusside, respectively. IBD-MPs decreased the contraction to serotonin (5-HT) compared to saline that was completely prevented in the presence of L-NA. Moreover, aorta from mice treated with IBD-MPs displayed increase NO production. Interestingly, the ability of NS-398 to reduce 5-HT-induced contraction in control mice was abolished in vessels taken from mice treated with IBD-MPs. Although IBD-MPs decreased O2- production in the aorta, the O2- scavenger MnTMPyP reduced the contraction to 5-HT in an identical manner in aorta from both control and IBD-MPs treated mice. The present study provides evidence of the capacity of IBD-MPs to induce endothelial dysfunction and vascular hyporeactivity. These effects result from a subtle alteration of the balance between NO, reactive oxygen species and metabolites from COX-2. They underscore the participation of MPs in the course of vascular alterations in this disease. (Partially supported by Ferring France Laboratories)

Increase in circulating microparticles in inflammatory bowel disease patients induces vascular alterations

Among the proposed hypothesis for inflammatory bowel disease (IBD) pathogenesis, a vascular cause has been suggested, mostly in reference to anatomic and pathological studies. We previously reported in small mesenteric arteries from Crohn's disease patients a balance between vasoconstrictor products from cyclooxygenase and unidentified vasodilatory products that maintained vascular reactivity in a physiological range despite an increase of circulatory cytokines in these patients (Tabernero et al., Circulation, 2003). Microparticles (MPs) are membrane vesicles released during cell activation and apoptosis. Elevated levels of circulating MPs have been detected in pathologic conditions and their increase has been associated with disease activity and/or prognosis. We investigated whether MPs from IBD patients may play a role in the regulation of endothelial function and vascular reactivity in this disease. Blood samples were obtained either from IBD patients as well as age and sex-matched healthy subjects. MPs concentration and origin were assessed by flow cytometry using specific antibodies. Male Swiss mice were injected intravenously with MPs from IBD patients or with saline solution and sacrified after 24hours. Endothelial function and vascular reactivity were studied on aortic rings and small mesenteric resistance arteries (SMA) by myography and arteriography, respectively. Patients with IBD displayed increased circulating levels of MPs compared to healthy subjects including those from procoagulant, platelet and activated platelet, endothelial, leukocyte and erythrocyte origins. In aorta, MPs from IBD patients compared to saline significantly reduced both endothelium-dependent relaxation to acetylcholine and contraction to serotonin. In SMA, although MPs from IBD patients did not affect flow-induced dilation, a reduced NO-component that was completely compensated by the endothelium-derived hyperpolarizing factor-component of the response was highlighted. Besides, MPs from IBD did not affect myogenic tone in SMA. These results provide further evidence of increased circulating levels of MPs in patients with IBD. MPs origin may play a role in enhanced coagulation and inflammatory states reported in IBD patients. Finally, MPs from IBD patients influence both endothelial dysfunction and vascular hyporeactivity in the experimental model used.(Partially supported by Ferring France Laboratories)

Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium.

Mucormycosis is a difficult to diagnose rare disease with high morbidity and mortality. Diagnosis is often delayed, and disease tends to progress rapidly. Urgent surgical and medical intervention is lifesaving. Guidance on the complex multidisciplinary management has potential to improve prognosis, but approaches differ between health-care settings. From January, 2018, authors from 33 countries in all United Nations regions analysed the published evidence on mucormycosis management and provided consensus recommendations addressing differences between the regions of the world as part of the "One World One Guideline" initiative of the European Confederation of Medical Mycology (ECMM). Diagnostic management does not differ greatly between world regions. Upon suspicion of mucormycosis appropriate imaging is strongly recommended to document extent of disease and is followed by strongly recommended surgical intervention. First-line treatment with high-dose liposomal amphotericin B is strongly recommended, while intravenous isavuconazole and intravenous or delayed release tablet posaconazole are recommended with moderate strength. Both triazoles are strongly recommended salvage treatments. Amphotericin B deoxycholate is recommended against, because of substantial toxicity, but may be the only option in resource limited settings. Management of mucormycosis depends on recognising disease patterns and on early diagnosis. Limited availability of contemporary treatments burdens patients in low and middle income settings. Areas of uncertainty were identified and future research directions specified

Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium

Mucormycosis is a difficult to diagnose rare disease with high morbidity and mortality. Diagnosis is often delayed, and disease tends to progress rapidly. Urgent surgical and medical intervention is lifesaving. Guidance on the complex multidisciplinary management has potential to improve prognosis, but approaches differ between health-care settings. From January, 2018, authors from 33 countries in all United Nations regions analysed the published evidence on mucormycosis management and provided consensus recommendations addressing differences between the regions of the world as part of the “One World One Guideline” initiative of the European Confederation of Medical Mycology (ECMM). Diagnostic management does not differ greatly between world regions. Upon suspicion of mucormycosis appropriate imaging is strongly recommended to document extent of disease and is followed by strongly recommended surgical intervention. First-line treatment with high-dose liposomal amphotericin B is strongly recommended, while intravenous isavuconazole and intravenous or delayed release tablet posaconazole are recommended with moderate strength. Both triazoles are strongly recommended salvage treatments. Amphotericin B deoxycholate is recommended against, because of substantial toxicity, but may be the only option in resource limited settings. Management of mucormycosis depends on recognising disease patterns and on early diagnosis. Limited availability of contemporary treatments burdens patients in low and middle income settings. Areas of uncertainty were identified and future research directions specified. © 2019 Elsevier Lt

Features of cryptococcosis among 652 HIV-seronegative individuals in France: a cross-sectional observational study (2005-2020)

International audienceObjectives: We aimed to describe features and outcomes of cryptococcosis among HIV-seronegative individuals in a large surveillance network for cryptococcosis in France.Methods: We included incident cases of cryptococcosis in HIV-seronegative individuals from 2005 to 2020. We compared patient characteristics, disease presentations, cryptococcal antigen (CrAg) results, and induction antifungal treatments according to underlying disease. We examined factors associated with 90-day mortality. Among patients with disseminated infections, we investigated whether receipt of flucytosine and polyene combination was associated with lower mortality.Results: Among 652 individuals, 209 (32.1%) had malignancy, 130 (19.9%) were solid-organ transplant (SOT) recipients, 204 (31.3%) had other immunocompromising conditions, and 109 (16.7%) had no reported underlying factor. The commonest presentations were disseminated infections (63.3%, 413/652) and isolated pulmonary infections (25.3%, 165/652). SOT patients were most likely to have disseminated infections and a positive serum CrAg result. Patients with malignancy were older and less likely to receive a flucytosine-containing regimen for disseminated infections than others (58.7%, 78/133 vs. 73.2%, 194/265, p=0.029). The crude 90-day case-fatality ratio was 27.2% (95%CI: 23.5%-31.1%). Age ≥60 years (aOR: 2.75 [1.78-4.26], p<0.001), meningitis/fungaemia (aOR: 4.79 [1.80-12.7], p=0.002), and malignancy (aOR: 2.4 [1.14-5.07], p=0.02) were associated with higher 90-day mortality. Receipt of flucytosine and polyene combination was associated with lower 90-day mortality (aOR: 0.40 [0.23-0.71], p=0.002) in multivariable analysis and inverse probability of treatment weighted analysis (aOR: 0.45 [0.25-0.80], p=0.006).Conclusions: HIV-seronegative individuals with cryptococcosis comprise a wide range of underlying conditions with different presentations and outcomes, requiring a tailored approach to diagnosis and management