Protective effects of cyclosporin-A in splanchnic artery occlusion shock

Cyclosporin A (CsA) is an immunosuppressant drug that inhibits nitric oxide (NO) synthase induction in vascular smooth muscle cells. Splanchnic artery occlusion (SAO) shock is a lethal type of shock characterized by a marked vascular dysfunction in which the L-arginine/nitric oxide pathway plays an important role. We investigated whether CsA exerts protective effects in SAO shock by interfering with the L-arginine/nitric oxide pathway. Male anaesthetized rats (n=156) were subjected to clamping of the splanchnic arteries for 45 min. This surgical procedure resulted in an irreversible state of shock (SAO shock). Sham operated animals were used as controls. SAO shocked rats had a decreased survival (86+/-6 min, while sham shocked rats survived more than 240 min), marked hypotension, increased serum levels of TNF-alpha, enhanced plasma nitrite/nitrate concentrations (75+/-7.1 microM; sham shocked rats=1.6+/-0.5 microM) and enhanced inducible NO synthase (iNOS) protein induction and activity in the aorta. Moreover aortic rings from shocked rats showed a marked hyporeactivity to phenylephrine (PE, 1 nM - 10 microM). CsA (0.25, 0.5 and 1 mg kg(-1), 5 min after reperfusion) increased survival rate (SAO+CsA=236+/-9 min following the highest dose), reverted the marked hypotension, reduced plasma nitrite/nitrate concentration (11+/-5.2 microM following the highest dose), restored to control values the hyporeactivity to PE, and blunted iNOS protein induction and activity in aortic rings. The present data indicate that in an experimental rat model CsA may have antishock properties related to inhibition of L-arginine/nitric oxide pathway.     

The phytoestrogen alpha-zearalenol reverses endothelial dysfunction induced by oophorectomy in rats

It has been shown recently that alpha-zearalenol, a resorcyclic acid lactone, prevents bone loss in a rat model of postmenopausal bone loss. We have therefore investigated the effects of this phytoestrogen on endothelial dysfunction induced by estrogen deficiency in rats. Female mature Sprague-Dawley rats underwent a bilateral oophorectomy (OVX rats). Sham-operated animals (sham OVX rats) were used as controls. Three weeks after surgery, animals were randomized to the following treatments: alpha-zearalenol (1 mg/kg/day, i.m., for 4 weeks), 17beta-estradiol (20 microg/kg/day, i.m., for 4 weeks), or their vehicle (100 microl, i.m., of cottonseed oil). Two other groups of rats were treated with alpha-zearalenol or 17beta-estradiol plus the pure estrogen receptor antagonist ICI 182780 (2.5 mg/kg/day, i.m., for 4 weeks). Mean arterial blood pressure (MAP), heart rate (HR), total plasma cholesterol, plasma estradiol, and plasma alpha-zearalenol were studied. We also investigated endothelial-dependent (acetylcholine, 10 nM to 10 microM) and endothelial-independent (sodium nitroprusside, 15 nM to 30 nM) relaxation of aortic rings, as well as N(G)-methyl-L-arginine (L-NMA: 10 to 100 microM)-induced vasoconstriction and calcium-dependent nitric oxide synthase (cNOS) activity in homogenates of lungs taken from both sham OVX rats and OVX rats. Untreated OVX rats had, compared with sham OVX animals, unchanged body weight, MAP, HR, and plasma cholesterol. In contrast oophorectomy reduced plasma estradiol levels (OVX, 2 +/- 0.5 pg/ml; sham OVX, 35 +/- 6 pg/ml), impaired endothelial-dependent relaxation and blunted L-NMA-induced contraction (L-NMA 100 microM: sham OVX, 2.7 +/- 0.3 g/mg tissue; OVX, 1.3 +/- 0.1 g/mg tissue). Moreover OVX rats showed a reduced calcium-dependent NO synthase (cNOS) activity. Treatment with alpha-zearalenol or with 17beta-estradiol reverted the endothelial dysfunction and increased cNOS activity in lung homogenates. These effects were abolished by the pure estrogen receptor antagonist ICI 182780. Our data suggest that alpha-zearalenol improves endothelial-dependent relaxation in OVX rats through an estrogen receptor-mediated effect.     

Trehalose: a biophysics approach to modulate the inflammatory response during endotoxic shock

We evaluated the effects of trehalose against endotoxic shock, a condition in which the loss of bio-membrane integrity plays a pivotal role. In addition we performed a biophysics experiment by Quasi Elastic Neutron Scattering (QENS) study, to investigate whether the membrane stability effect of trehalose might be correlated with its high capability to switch-off the water diffusive dynamics and, hence, the kinetic mechanisms of interaction. Endotoxic shock was induced in male rats by a single injection of Salmonella enteritidis lipopolysaccharide (LPS; 20 mg/kg/i.p.). Thirty minutes before and 2 h after LPS injection, the animals were randomized to receive vehicle (1 ml/kg/i.p. 0.9%NaCl), sucrose (1 g/kg/i.p.) or trehalose (1 g/kg/i.p.). Mean arterial blood pressure, Nuclear Factor-kappass (NF-kappaB) binding activity, Ikappa-Balpha and Toll-like receptor-4 (TLR-4) activation were evaluated in both liver and lung. Plasmatic tumor necrosis factor-alpha (TNF-alpha), Interleukin-1 (IL-1), Interleukin-6 (IL-6) and malondialdehyde (MDA) were also investigated. We studied liver injury by means of blood alanine aminotransferase activity (ALT); inducible nitric oxide synthase (iNOS) expression, myeloperoxidase (MPO) activity and tissue edema evaluation. Lung injury was investigated by means of tissue monocyte chemoattractant protein-1 (MCP-1) levels, MPO activity, iNOS expression and edema formation. Trehalose reduced hypotension, NF-kappaB binding activity, IkappaBalpha protein loss and TLR-4 activation. In addition trehalose reduced TNF-alpha, IL-1, IL-6 and MDA levels. Trehalose also blunted liver and lung injury. QENS measurements showed also that trehalose possesses a high "switching off" capability. Sucrose did not modify endotoxic shock-induced sequelae. Trehalose blocked the inflammatory cascade triggered by endotoxin shock, stabilizing the bio-membranes and switching off the water diffusive dynamics.     

Muscle fat-fraction and mapping in Duchenne muscular dystrophy: evaluation of disease distribution and correlation with clinical assessments

Purpose

To examine the usefulness of dual-echo dual-flip angle spoiled gradient recalled (SPGR) magnetic resonance imaging (MRI) technique in quantifying muscle fat fraction (MFF) of pelvic and thighs muscles as a marker of disease severity in boys with Duchenne muscular dystrophy (DMD), by correlating MFF calculation with clinical assessments. We also tried to identify characteristic patterns of disease distribution.

Materials and methods

Twenty consecutive boys (mean age, 8.6?years?±?2.3 [standard deviation, SD]; age range, 5–15?years; median age, 9?years;) with DMD were evaluated using a dual-echo dual-flip angle SPGR MRI technique, calculating muscle fat fraction (MFF) of eight muscles in the pelvic girdle and thigh (gluteus maximus, adductor magnus, rectus femoris, vastus lateralis, vastus medialis, biceps femoris, semitendinosus, and gracilis). Color-coded parametric maps of MFF were also obtained. A neurologist who was blinded to the MRI findings performed the clinical assessments (patient age, Medical Research Council score, timed Gower score, time to run 10?m). The relationships between mean MFF and clinical assessments were investigated using Spearman’s rho coefficient. Positive and negative correlations were evaluated and considered significant if the P value was?Results The highest mean MFF was found in the gluteus maximus (mean, 46.3 %?±?24.5 SD), whereas the lowest was found in the gracilis muscle (mean, 2.7 %?±?4.7 SD). Mean MFF of the gluteus maximus was significantly higher than that of the other muscles (P?P?P?P?P?Conclusion Muscle fat fraction calculation and mapping using the dual-echo dual-flip angle SPGR MRI technique are useful markers of disease severity and permit patterns of disease distribution to be identified in patients with DMD.     

Effects of genistein aglycone in osteoporotic, ovariectomized rats: a comparison with alendronate, raloxifene and oestradiol

Background and purpose:     

Semiautomatic Quantification of Left Ventricular Function by Two‐Dimensional Feature Tracking Imaging Echocardiography. A Comparison Study with Cardiac Magnetic Resonance Imaging

Objective: To evaluate the accuracy of a semiautomatic quantification of left ventricular (LV) volumes and ejection fraction (EF) using two‐dimensional (2D) feature tracking imaging (FTI). Methods: Thirty‐four consecutive subjects (11 patients with dilated cardiomyopathy, 13 with hypertrophic cardiomyopathy, and 10 subjects with no cardiac disease) underwent, on the same day, trans‐thoracic echocardiography (TTE) examination, FTI, and cardiac magnetic resonance imaging (MRI), as gold standard, in order to quantify LV volumes and EF. The echocardiographic quantification of LV volumes and EF was determined from four‐ and two‐chamber views using both standard TTE Biplane Simpson's method and a semiautomatic border detection based on FTI. Furthermore, the time for data analysis for each method was measured. Results: The time required for semiautomatic analysis of volumes and EF was significantly lower (P < 0.0001) by FTI (71 seconds) in comparison with standard biplane Simpson's method (93 seconds). LV volumes obtained by FTI were significant underestimated (P < 0.001) in comparison with MRI. Bland‐Altman analysis of EDV and ESV using FTI and cardiac MRI showed a low level of agreement for EDV (mean difference = 40.8; SD = 39) and ESV (mean difference = 38.1; SD = 42). On the contrary, no significant difference between FTI and MRI in assessing the LVEF was found; furthermore, a very low bias (2 ± 12) by Bland‐Altman analysis was found between FTI and cardiac MRI for the quantification of EF. Conclusion: Semiautomatic quantification of LV volumes using FTI allows an accurate, rapid, easy and reliable assessment of LV EF and a rough estimation of LV volumes. (Echocardiography 2010;27:791‐797)