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)

Effectiveness of delayed-release dimethyl fumarate on patient-reported outcomes and clinical measures in patients with relapsing-remitting multiple sclerosis in a real-world clinical setting : PROTEC

Background: Patient-reported outcomes (PRO) and clinical outcomes give a broad assessment of relapsing-remitting multiple sclerosis (RRMS) disease. Objective: The aim is to evaluate the effectiveness of delayed-release dimethyl fumarate (DMF) on disease activity and PROs in patients with RRMS in the clinic. Methods: PROTEC, a phase 4, open-label, 12-month observational study, assessed annualized relapse rate (ARR), proportion of patients relapsed, and changes in PROs. Newly diagnosed and early MS (≤3.5 EDSS and ≤1 relapse in the prior year) patient subgroups were evaluated. Results: Unadjusted ARR at 12 months post-DMF versus 12 months before DMF initiation was 75% lower (0.161 vs. 0.643, p < 0.0001) overall (n = 1105) and 84%, 77%, and 71% lower in newly diagnosed, ≤3.5 EDSS, and ≤1 relapse subgroups, respectively. Overall, 88% of patients were relapse-free 12 months after DMF initiation (84%, newly diagnosed; 88%, ≤3.5 EDSS; 88%, ≤1 relapse). PRO measures for fatigue, treatment satisfaction, daily living, and work improved significantly over 12 months of DMF versus baseline. Conclusion: At 12 months after versus 12 months before DMF initiation, ARR was significantly lower, the majority of patients were relapse-free, and multiple PRO measures showed improvement (overall and for subgroups), suggesting that DMF is effective based on clinical outcomes and from a patient perspective. Clinical trial: A Study Evaluating the Effectiveness of Tecfidera (Dimethyl Fumarate) on Multiple Sclerosis (MS) Disease Activity and Patient-Reported Outcomes (PROTEC), NCT01930708, https://clinicaltrials.gov/ct2/show/NCT01930708

Breakthrough invasive fungal disease in patients receiving posaconazole primary prophylaxis: a 4-year study

AbstractPosaconazole (PSC) is currently recommended as primary prophylaxis in neutropenic patients with acute myeloid leukaemia (AML) and in allogenic haematopoietic stem cell transplantation (AHSCT) recipients with graft-versus-host disease (GVHD). Studies focusing on breakthrough invasive fungal disease (IFD) upon PSC prophylaxis show disparate results. In order to evaluate the incidence of IFD in patients on PSC prophylaxis and identify IFD risk factors, we carried out a retrospective study of all consecutive patients on PP from January 2007 to December 2010 in our hospital. Breakthrough IFDs were identified from the database of the central pharmacy and the French administrative database (PMSI), registering final medical diagnoses of hospitalized patients. Medical data were reviewed to study proven or probable IFD, according to EORTC/MSG definition. PSC plasma concentrations (PPC) were also retrieved. Poisson models were used for statistical analysis. Two hundred and seventy-nine patients received PSC prophylaxis for a median duration of 1.4 months (range 0.2–17.9). Proven (n = 6) or probable (n = 3) IFDs were diagnosed in nine cases (3.2%). IFD incidence rate per 100 person-month was 1.65 (95% CI, 0.79–2.97). IFDs were candidaemia (Candida glabrata, n = 2), pulmonary invasive aspergillosis (n = 3), disseminated fusariosis (n = 2) and pulmonary mucormycosis (n = 2). Seven deaths were reported, directly related to IFD in three patients (33.3%). First dosage of PPC under 0.3 mg/L was the single significant risk factor for IFD (RR, 7.77; 95% CI, 1.30–46.5; p 0.025). Breakthrough IFD in patients receiving PSC prophylaxis is rare but associated with a poor outcome. Low PSC plasma concentrations are associated with an increased risk of IFD

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)

Collisional kinetics of non-uniform electric field, low-pressure, direct-current discharges in H2_{2}

A model of the collisional kinetics of energetic hydrogen atoms, molecules, and ions in pure H$_2$ discharges is used to predict H$_\alpha$ emission profiles and spatial distributions of emission from the cathode regions of low-pressure, weakly-ionized discharges for comparison with a wide variety of experiments. Positive and negative ion energy distributions are also predicted. The model developed for spatially uniform electric fields and current densities less than $10^{-3}$ A/m$^2$ is extended to non-uniform electric fields, current densities of $10^{3}$ A/m$^2$, and electric field to gas density ratios $E/N = 1.3$ MTd at 0.002 to 5 Torr pressure. (1 Td = $10^{-21}$ V m$^2$ and 1 Torr = 133 Pa) The observed far-wing Doppler broadening and spatial distribution of the H$_\alpha$ emission is consistent with reactions among H$^+$, H$_2^+$, H$_3^+$, and H$^-H$ ions, fast H atoms, and fast H$_2$ molecules, and with reflection, excitation, and attachment to fast H atoms at surfaces. The H$_\alpha$ excitation and H$^-$ formation occur principally by collisions of fast H, fast H$_2$, and H$^+$ with H$_2$. Simplifications include using a one-dimensional geometry, a multi-beam transport model, and the average cathode-fall electric field. The H$_\alpha$ emission is linear with current density over eight orders of magnitude. The calculated ion energy distributions agree satisfactorily with experiment for H$_2^+$ and H$_3^+$, but are only in qualitative agreement for H$^+$ and H$^-$. The experiments successfully modeled range from short-gap, parallel-plane glow discharges to beam-like, electrostatic-confinement discharges.Comment: Submitted to Plasmas Sources Science and Technology 8/18/201

UV continuum emission and diagnostics of hydrogen-containing non-equilibrium plasmas

For the first time the emission of the radiative dissociation continuum of the hydrogen molecule ($a^{3}\Sigma_{g}^{+} \to b^{3}\Sigma_{u}^{+}$ electronic transition) is proposed to be used as a source of information for the spectroscopic diagnostics of non-equilibrium plasmas. The detailed analysis of excitation-deactivation kinetics, rate constants of various collisional and radiative transitions and fitting procedures made it possible to develop two new methods of diagnostics of: (1) the ground $X^{1}\Sigma_{g}^{+}$ state vibrational temperature $T_{\text{vib}}$ from the relative intensity distribution, and (2) the rate of electron impact dissociation (d[\mbox{H_{2}}]/dt)_{\text{diss}} from the absolute intensity of the continuum. A known method of determination of $T_{\text{vib}}$ from relative intensities of Fulcher-$\alpha$ bands was seriously corrected and simplified due to the revision of $d \to a$ transition probabilities and cross sections of $d \gets X$ electron impact excitation. General considerations are illustrated with examples of experiments in pure hydrogen capillary-arc and H$_{2}$+Ar microwave discharges.Comment: REVTeX, 25 pages + 12 figures + 9 tables. Phys. Rev. E, eprint replaced because of resubmission to journal after referee's 2nd repor

Axial light emission and Ar metastable densities in a parallel plate dc micro discharge in steady state and transient regimes

Axial emission profiles in a parallel plate dc micro discharge (feedgas: argon; discharge gap d=1mm; pressure p=10Torr) were studied by means of time resolved imaging with a fast ICCD camera. Additionally, volt-ampere (V-A) characteristics were recorded and Ar* metastable densities were measured by tunable diode laser absorption spectroscopy (TDLAS). Axial emission profiles in the steady state regime are similar to corresponding profiles in standard size discharges (d=1cm, p=1Torr). For some discharge conditions relaxation oscillations are present when the micro discharge switches periodically between low current Townsend-like mode and normal glow. At the same time the axial emission profile shows transient behavior, starting with peak distribution at the anode, which gradually moves towards the cathode during the normal glow. The development of argon metastable densities highly correlates with the oscillating discharge current. Gas temperatures in the low current Townsend-like mode (T= 320-400K) and the high current glow mode (T=469-526K) were determined by the broadening of the recorded spectral profiles as a function of the discharge current.Comment: submitted to Plasma Sources Sci. Techno

Pyoderma Gangrenosum Associated with Sclerosing Cholangitis, Type 1 Diabetes Mellitus and Ulcerative Colitis

We describe the case of a 22-year-old black female with type 1 diabetes mellitus diagnosed when she was 12 years old. She first presented (March 1994) with pustules and ulcerations on the upper and lower limbs, trunk and scalp at the age 17. The diagnosis of pyoderma gangrenosum was made. Since presentation, changes in liver function were detected and subsequent study led to the diagnosis of sclerosing cholangitis. The diagnosis of ulcerative colitis was made after colonoscopy. Partial response was obtained with minocycline and clofazimine, but treatment with 5-aminosalicylic acid achieved no improvement of the ulcerations. Liver transplantation, followed by immunosuppressive therapy led to complete regression of the cutaneous lesions