NO transfer reactions between protein and peptide cysteines have been proposed to represent regulated signaling processes. We used the pharmaceutical antioxidant N-acetylcysteine (NAC) as a bait reactant to measure NO transfer reactions in blood and to study the vascular effects of these reactions in vivo. NAC was converted to S-nitroso-N-acetylcysteine (SNOAC), decreasing erythrocytic S-nitrosothiol content, both during wholeblood deoxygenation ex vivo and during a 3-week protocol in which mice received high-dose NAC in vivo. Strikingly, the NAC-treated mice developed pulmonary arterial hypertension (PAH) that mimicked the effects of chronic hypoxia. Moreover, systemic SNOAC administration recapitulated effects of both NAC and hypoxia. eNOS-deficient mice were protected from the effects of NAC but not SNOAC, suggesting that conversion of NAC to SNOAC was necessary for the development of PAH. These data reveal an unanticipated adverse effect of chronic NAC administration and introduce a new animal model of PAH. Moreover, evidence that conversion of NAC to SNOAC during blood deoxygenation is necessary for the development of PAH in this model challenges conventional views of oxygen sensing and of NO signaling.Introduction NO transfer reactions between protein and peptide cysteines have been proposed to represent regulated signaling processes (1, 2). For example, NO transfer from deoxygenated erythrocytes to glutathione ex vivo forms S-nitrosoglutathione (GSNO) (3). GSNO can signal acute vascular and central ventilatory effects characteristic of oxyhemoglobin desaturation (3-4) that are regulated by γ-glutamyl transpeptidase (GGT), GSNO reductase (GSNOR), and other enzymes (1, 3-6). However, direct measurement of S-nitrosothiol signaling in vivo has proven challenging because of the metabolism and tissue-specific localization of endogenous S-nitrosothiol species (1, 3, 4, 6). We have addressed these challenges by using N-acetylcysteine (NAC) as a bait reactant, allowing the stable NO transfer product, S-nitroso-N-acetylcysteine (SNOAC), to be distinguished by mass spectrometry (MS) from endogenous S-nitrosothiols. We report that NAC is converted to SNOAC in mice in vivo. Furthermore, chronic, systemic administration of either NAC or SNOAC to mice causes hypoxia-mimetic pulmonary arterial hypertension (PAH). These data reveal a previously unappreciated vascular toxicity of NAC and of S-nitrosothiols. Moreover, they suggest that S-nitrosothiol transfer reactions can signal hypoxia in vivo.PAH is characterized by increased pressure in the pulmonary arteries (PAs), increased RV weight, and thickening and remodeling of small PAs. Untreated human PAH can progress to right

Type 1 diabetes mellitus (T1D) is a chronic, multifactorial autoimmune disease that involves the progressive destruction of pancreatic β-cells, ultimately resulting in the loss of insulin production and secretion. The goal of clinical intervention is to prevent or arrest the onset and progression of autoimmunity, reverse β-cell destruction, and restore glycometabolic and immune homeostasis. Despite promising outcomes observed with islet transplantation and advancements in immunomodulatory therapies, the need for an effective cell replacement strategy for curing T1D still persists. Stem cell therapy offers a solution to the cited challenges of islet transplantation. While the regenerative potential of stem cells can be harnessed to make available a self-replenishing supply of glucose-responsive insulin-producing cells, their immunomodulatory properties may potentially be used to prevent, arrest, or reverse autoimmunity, ameliorate innate/alloimmune graft rejection, and prevent recurrence of the disease. Herein, we discuss the therapeutic potential of stem cells derived from a variety of sources for the cure of T1D, for example, embryonic stem cells, induced pluripotent stem cells, bone marrow-derived hematopoietic stem cells, and multipotent mesenchymal stromal cells derived from bone marrow, umbilical cord blood, and adipose tissue. The benefits of combinatorial approaches designed to ensure the successful clinical translation of stem cell therapeutic strategies, such as approaches combining effective stem cell strategies with islet transplantation, immunomodulatory drug regimens, and/or novel bioengineering techniques, are also discussed. To conclude, the application of stem cell therapy in the cure for T1D appears extremely promising.

W La Revue canadienne de psychiatrie, vol 55, no 12, décembre 2010 784Objectives: About 50% of men with antisocial personality disorder (APD) present a comorbid anxiety disorder. Historically, it was thought that anxiety limited criminal activity and the development of APD, but recent evidence suggests that heightened responsiveness to threat may lead to persistent violent behaviour. Our study aimed to determine the prevalence of APD comorbid with anxiety disorders among offenders and the association of these comorbid disorders with violent offending.Method: A random sample of 495 male penitentiary inmates completed an interview using the Diagnostic Interview Schedule. After excluding men with psychotic disorders, 279 with APD were retained. All authorized access to their criminal records.Results: Two-thirds of the prisoners with APD presented a lifetime anxiety disorder. Among them, one-half had the onset of their anxiety disorder before they were aged 16 years. Among the offenders with APD, those with, compared with those without, anxiety disorders presented significantly more symptoms of APD, were more likely to have begun their criminal careers before they were aged 15 years, to have diagnoses of alcohol and (or) drug abuse and (or) dependence, and to have experienced suicidal ideas and attempts. While there were no differences in the mean number of convictions for violent offences between APD prisoners with and without anxiety disorders, more of those with anxiety disorders had been convicted of serious crimes involving interpersonal violence. Conclusions:Among men with APD, a substantial subgroup present life-long anxiety disorders. This pattern of comorbidity may reflect a distinct mechanism underlying violent behaviour and signalling the need for specific treatments.Can J Psychiatry. 2010;55(12):784-791. Clinical Implications· Among male offenders with APD, two-thirds presented lifetime anxiety disorders. · Among 50% of male offenders with APD and anxiety disorders, the anxiety disorders had onset before they were aged 16 years. · APD plus anxiety disorders may constitute a subtype with distinctive treatment needs and etiology. Limitations· Interrater reliability estimates for diagnoses could not be read from old computer tapes. · The syndrome of psychopathy was not assessed. · The Diagnostic and Statistical Manual of Mental Disorders (DSM), Third Edition, Revised, not DSM-IV, criteria for diagnoses were used.

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Clinical islet transplantation is a β-cell replacement strategy that represents a possible definitive intervention for patients with type 1 diabetes, offering substantial benefits in terms of lowering daily insulin requirements and reducing incidences of debilitating hypoglycemic episodes and unawareness. Despite impressive advances in this field, a limiting supply of islets, inadequate means for preventing islet rejection, and the deleterious diabetogenic and nephrotoxic side effects associated with chronic immunosuppressive therapy preclude its wide-spread applicability. Islet transplantation however allows a window of opportunity for attempting various therapeutic manipulations of islets prior to transplantation aimed at achieving superior transplant outcomes. In this paper, we will focus on the current status of various immunosuppressive and cellular therapies that promote graft function and survival in preclinical and clinical islet transplantation with special emphasis on the tolerance-inducing capacity of regulatory T cells as well as the β-cells regenerative capacity of stem cells.

Activation of adenosine A2A receptors (A2AR) reduces inflammation by generally inhibiting the activation of pro-inflammatory cells, decreasing endothelial adhesion molecule expression and reducing the release of proinflammatory cytokine mediators. Numerous preclinical studies using selective A2AR agonists, antagonists, A2AR knockout as well as chimeric mice have suggested the therapeutic potential of A2AR agonists for the treatment of ischemia reperfusion injury (IRI) and autoimmune diseases. This review summarizes the immunosuppressive actions of A2AR agonists in murine IRI models of liver, kidney, heart, lung and CNS, and gives details on the cellular effects of A2AR activation in neutrophils, macrophages, dendritic cells, natural killer cells, NKT cells, T effector cells and CD4+CD25+FoxP3+ T regulatory cells. This is discussed in the context of cytokine mediators involved in inflammatory cascades. Whilst the role of adenosine receptor agonists in various models of autoimmune disease has been well-documented, very little information is available regarding the role of A2AR activation in type 1 diabetes mellitus (T1DM). An overview of the pathogenesis of T1DM as well as early islet graft rejection in the immediate peri-transplantation period offers insight regarding the use of A2AR agonists as a beneficial intervention in clinical islet transplantation, promoting islet graft survival, minimizing early islet loss and reducing the number of islets required for successful transplantation, thereby increasing the availability of this procedure to a greater number of recipients. In summary, the use of A2AR agonists as a clinical intervention in IRI and as an adjunct to clinical immunesuppressive regimen in islet transplantation is highlighted.

Activation of adenosine A(2A) receptors inhibits inflammation in ischemia/reperfusion injury, and protects against cell damage at the injury site. Following transplantation 50% of islets die due to inflammation and apoptosis. This study investigated the effects of adenosine A(2A) receptor agonists (ATL146e and ATL313) on glucose-stimulated insulin secretion (GSIS) in vitro and transplanted murine syngeneic islet function in vivo. Compared to vehicle controls, ATL146e (100 nM) decreased insulin stimulation index [SI, (insulin)(high glucose)/(insulin)(low glucose)] (2.36 +/- 0.22 vs. 3.75 +/- 0.45; n = 9; p < 0.05). Coculture of islets with syngeneic leukocytes reduced SI (1.41 +/- 0.17; p < 0.05), and this was restored by ATL treatment (2.57 +/- 0.18; NS). Addition of a selective A(2A)AR antagonist abrogated ATL's protective effect, reducing SI (1.11 +/- 0.42). ATL treatment of A(2A)AR(+/+) islet/A(2A)AR(-/-) leukocyte cocultures failed to protect islet function (SI), implicating leukocytes as likely targets of A(2A)AR agonists. Diabetic recipient C57BL/6 mice (streptozotocin; 250 mg/kg, IP) received islet transplants to either the renal subcapsular or hepatic-intraportal site. Recipient mice receiving ATL therapy (ATL 146e or ATL313, 60 ng/kg/min, IP) achieved normoglycemia more rapidly than untreated recipients. Histological examination of grafts suggested reduced cellular necrosis, fibrosis, and lymphocyte infiltration in agonist-treated animals. Administration of adenosine A(2A) receptor agonists (ATL146e or ATL313) improves in vitro GSIS by an effect on leukocytes, and improves survival and functional engraftment of transplanted islets by inhibiting inflammatory islet damage in the peritransplant period, suggesting a potentially significant new strategy for reducing inflammatory islet loss in clinical transplantation.

Type 1 diabetes mellitus is an autoimmune disease that is characterized by the destruction of the islets of Langerhans cells which produce insulin. The current gold standard treatment is exogenous insulin injection, but this is onerous for the patients, and can lead to severe complications. Another approach involves transplanting pancreatic islet cells in order to restore endogenous insulin production under physiologic regulation. Although there has been some success with this treatment plan, there have been several hurdles. The largest hurdle is improving the 5 year survival of the graft, which is currently at 10%. In order to do so, there has been research into better locations for the graft, better isolation techniques, alternate immune suppression regimens, and novel transplantation methodologies utilizing encapsulated grafts. Another hurdle for pancreatic islet transplantation is that current methodologies require islets from several pancreata in order to create one successful graft, which leads to difficulties since there is a limited supply. However, there has been research looking into single donor transplants and porcine xenografts to increase the supply and address this problem. In this article, we review the current state of research regarding pancreatic islet transplantation.