Protective effects of M40403, a superoxide dismutase mimetic, in a rodent model of colitis.

Inflammatory bowel disease is characterised by oxidative and nitrosative stress, leukocyte infiltration, and up-regulation of intercellular adhesion molecule 1 (ICAM-1) expression in the colon. The aim of the present study was to examine the effects of M40403, a superoxide dismutase mimetic, in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of trinitrobenzene sulfonic acid (TNBS). Rats experienced bloody diarrhoea and significant loss of body weight. At 4 days after TNBS administration, the colon damage was characterised by areas of mucosal necrosis. Neutrophil infiltration (indicated by myeloperoxidase activity in the mucosa) was associated with up-regulation of ICAM-1 and expression of P-selectin and high levels of malondialdehyde. Immunohistochemistry for nitrotyrosine and poly (ADP-ribose) synthetase showed an intense staining in the inflamed colon. Treatment with M40403 (5 mg/kg daily i.p.) significantly reduced the appearance of diarrhoea and the loss of body weight. This was associated with a remarkable amelioration of the disruption of the colonic architecture as well as a significant reduction of colonic myeloperoxidase activity and malondialdehyde levels. M40403 also reduced the appearance of nitrotyrosine and poly (ADP-ribose) synthetase immunoreactivity in the colon as well as reduced the up-regulation of ICAM-1 and the expression of P-selectin. The results of this study suggested that administration of a superoxide dismutase mimetic may be beneficial for treatment of inflammatory bowel disease.     

Cardiac magnetic resonance in cocaine-induced myocardial damage: cocaine,heart, and magnetic resonance

Heart Failure Reviews - The use of cocaine constitutes a major health problem. Cocaine use is associated with acute and chronic complications that might involve any system, the most common being...     

The Impact of IFN-γ Receptor on SLPI Expression in Active Tuberculosis: Association with Disease Severity

Interferon (IFN)-γ displays a critical role in tuberculosis (TB), modulating the innate and adaptive immune responses. Previously, we reported that secretory leukocyte protease inhibitor (SLPI) is a pattern recognition receptor with anti-mycobacterial activity against Mycobacterium tuberculosis (Mtb). Herein, we determined whether IFN-γ modulated the levels of SLPI in TB patients. Plasma levels of SLPI and IFN-γ were studied in healthy donors (HDs) and TB patients. Peripheral blood mononuclear cells from HDs and patients with TB or defective IFN-γ receptor 1* were stimulated with Mtb antigen and SLPI, and IFN-γR expression levels were measured. Both SLPI and IFN-γ were significantly enhanced in plasma from those with TB compared with HDs. A direct association between SLPI levels and the severity of TB was detected. In addition, Mtb antigen stimulation decreased the SLPI produced by peripheral blood mononuclear cells from HDs, but not from TB or IFN-γR patients. Neutralization of IFN-γ reversed the inhibition of SLPI induced by Mtb antigen in HDs, but not in TB patients. Furthermore, recombinant IFN-γ was unable to modify the expression of SLPI in TB patients. Finally, IFN-γR expression was lower in TB compared with HD peripheral blood mononuclear cells. These results show that Mtb-induced IFN-γ down-modulated SLPI levels by signaling through the IFN-γR in HDs. This inhibitory mechanism was not observed in TB, probably because of the low expression of IFN-γR detected in these individuals.Tuberculosis (TB) is among the most common causes of morbidity and mortality in patients with HIV infection. Although protective immunological mechanisms against Mycobacterium tuberculosis (Mtb) are not fully understood, resistance to mycobacterial infections is primarily mediated by the interaction of antigen-specific T cells and macrophages.^1,2 This interaction depends on the cross talk of cytokines produced by these cells, and interferon (IFN)-γ is essential for protection.^2,3 Thus, during the immune response of the host against Mtb, IFN-γ produced by type 1 helper T cells is recognized by its receptor on macrophages. The IFN-γ receptor (IFN-γR) is composed of two ligand-binding IFNGR1 chains associated with two signal-transducing IFNGR2 chains, and an associated signaling machinery.^2–5 IFN-γ binds to its receptor and activates macrophages to efficient killing of intracellular mycobacteria. In humans, the loss-of-function mutations in IFNGR1 or IFNGR2 genes are closely associated with severe susceptibility to poorly virulent mycobacteria highlighted in childhood.^4,6,7Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor secreted by inflammatory and epithelial cells, mainly in the respiratory tract mucosa, and it is primarily active against neutrophilic elastase, cathepsin G, trypsin, and chymotrypsin.⁸ The expression and secretion of SLPI are down-modulated during chronic obstructive pulmonary disease.^9–11 In addition, cathepsins B, L, and S and cigarette smoke exposure result in the cleavage and inactivation of SLPI.^12,13 Moreover, it has been demonstrated that IFN-γ is a prominent stimulator of cathepsins and matrix metalloproteinase-12 and an inhibitor of SLPI.¹⁴ Remarkably, SLPI may also function as an endogenous immunomodulatory, anti-inflammatory, and/or antimicrobial substance.^15–18 The antimicrobial effects of SLPI against several bacteria have been demonstrated.¹⁵ In particular, Nishimura et al¹⁷ described that recombinant mouse SLPI inhibited the growth of bacillus Calmette-Guérin (BCG) and Mtb through the disruption of the mycobacterial cell wall structure. Furthermore, we reported that human SLPI is a secreted pattern recognition receptor for mycobacteria that increases both the phagocytosis and killing of the pathogen.¹⁸ Remarkably, exposure of murine peritoneal macrophages to Mtb led to an increase in SLPI secretion.¹⁹ Thus, given the anti-inflammatory and anti-mycobacterial roles of SLPI in humans and taking into account the fact that SLPI is inhibited by IFN-γ,²⁰ a crucial cytokine in the protective immunity against Mtb, herein we studied the effect of IFN-γ on the expression of SLPI during human active disease.     

Implantable cardioverter-defibrillators in patients with arrhythmogenic right ventricular cardiomyopathy: the course of electronic parameters,clinical features,and complications during long-term follow-up

Purpose

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive cardiomyopathy characterized by myocardial atrophy and fibro-fatty replacement of the right ventricle (RV) and ventricular tachyarrhythmias in young patients. Our aim was to evaluate clinical course and electronic parameters in patients with implantable cardioverter-defibrillator (ICD) and ARVC, during long-term follow-up.

Methods and results

We report on 12 patients with ARVC (mean age 40?±?13 years) who were treated with ICD implantation in our center. Although several RV sites were tested for proper lead positions, the amplitude of R-wave at implantation was quite low (7.4?±?3.0 mV). After a mean follow-up of 91?±?28 months, R-wave amplitude significantly decreased to a mean value of 5.4?±?2.5 mV (p?=?0.03). We also found a noticeable, nearly significant increase in pacing threshold (p?=?0.052) and a moderate increase in defibrillation impedance (p?=?0.07). Six patients (46 %) experienced at least one appropriate ICD therapy; three patients (23 %) experienced inappropriate ICD shocks secondary to the supraventricular tachycardia, T-wave oversensing, and electromagnetic interference.

Conclusions

ICD in patients with ARVC has been demonstrated to be feasible and safe. In our case series, we found low R-wave amplitudes at implantation and a significant R-wave decrease during follow-up; a considerable and nearly significant increase in pacing threshold was also observed. These findings may be related to the progressive fibro-fatty replacement of RV myocardium. Multiple sites should be tested in the right ventricle if sensing or pacing values are not optimal, and all the electronic parameters should be carefully monitored throughout the entire follow-up.     

Characterization of polyphenols,lipids and dietary fibre from almond skins (Amygdalus communis L.)

Almond skins and blanch water are underutilized by-products of the almond processing industry. Nevertheless, they contain exploitable components that may contribute to the health benefits associated with almond consumption. We have compared natural almond skin powder (NS) prepared by a novel freeze-thawing method with blanched almond skin powder (BS). Microstructural studies were carried out, and we analyzed both types of almond skin for phenolic compounds (by HPLC), lipids (by solvent extraction), proteins (by micro-Kjeldahl), and fibre content (by the enzymatic-gravimetric AOAC method). Antioxidant activity (by measuring the reduction of the 2,2-diphenyl-1-picrylhydrazyl radical) was also monitored. We identified a combination of flavonols, flavan-3-ols, hydroxybenzoic acids and flavanones in NS, BS and in industrially obtained blanch water (BW). As expected, the total phenolic content was higher in NS compared to BW and BS, although the latter showed high antioxidant properties. Almond skins had high fibre content as well as significant amounts of lipid; both of these components may be relevant to fermentation in the large intestine. In addition, the processing of almond skins and blanch water clearly has economic potential for lowering the environmental impact of waste fill and pollution.     

Glycogen synthase kinase-3beta inhibitors protect against the organ injury and dysfunction caused by hemorrhage and resuscitation

Glycogen synthase kinase 3beta (GSK-3beta) is a serine/threonine protein kinase that has recently emerged as a key regulatory switch in the modulation of the inflammatory response. Dysregulation of GSK-3beta has been implicated in the pathogenesis of several diseases including sepsis. Here we investigate the effects of 2 chemically distinct inhibitors of GSK-3beta, TDZD-8 and SB216763, on the circulatory failure and the organ injury and dysfunction associated with hemorrhagic shock. Male Wistar rats were subjected to hemorrhage (sufficient to lower mean arterial blood pressure to 35 mmHg for 90 min) and subsequently resuscitated with shed blood for 4 h. Hemorrhage and resuscitation resulted in an increase in serum levels of (a) creatinine and, hence, renal dysfunction, and (b) alanine aminotransferase and aspartate aminotransferase and, hence, hepatic injury. Treatment of rats with either TDZD-8 (1 mg/kg, i.v.) or SB216763 (0.6 mg/kg, i.v.) 5 min before resuscitation abolished the renal dysfunction and liver injury caused by hemorrhagic shock. In addition, TDZD-8, but not SB216763, attenuated the increase caused by hemorrhage and resuscitation in plasma levels of the proinflammatory cytokine interleukin 6 and also of the anti-inflammatory cytokine interleukin 10. Neither of the GSK-3beta inhibitors however affected the delayed fall in blood pressure caused by hemorrhagic shock. Thus, we propose that inhibition of GSK-3beta may represent a novel therapeutic approach in the therapy of hemorrhagic shock.     

Searching for Arg201 mutations in the GNAS1 gene in Italian patients with McCune-Albright syndrome

McCune-Albright syndrome (MAS) is a rare disease caused by somatic postzygotic mutations at Arg201 in the GNAS1 gene that encodes for the Gsalpha protein. Arg201 mutations are gain-of-function mutations in affected tissues (including bone, skin, endocrine glands and other tissues) that result in the activation of cAMP. We used a polymerase chain reaction(PCR)-based technique for the selective enrichment and analysis of the Arg201 mutant allele in 27 different tissues from 24 Italian patients with one or more signs of MAS. Arg201 mutations were identified in 13 different tissues (48.1%) from 11 patients (45.8%). Mutation detection rates differed across the various types of tissue samples, and the mutation was not always found in every tissue sample from the same patient. To overcome problems in the analysis of mutations in somatic mosaicism, as occurs in MAS, a highly sensitive molecular technique should be applied, the most appropriate tissue source selected, and various affected tissues from the same patient analyzed.