ContextDiabetic muscle infarction (DMI) is a rare complication associated with poorly controlled diabetes mellitus. Less than 200 cases have been reported in the literature since it was first described over 45 years ago. There is no clear ‘standard of care’ for managing these patients.Evidence acquisitionPubMed searches were conducted for ‘diabetic muscle infarction’ and ‘diabetic myonecrosis’ from database inception through July 2014. All articles identified by these searches were reviewed in detail if the article text was available in English.Evidence synthesisThe current literature exists as case reports or small case series, with no prospective or higher-order treatment studies available. Thus, an evidence-based approach to data synthesis was difficult. The available literature is presented objectively with an attempt to describe clinically relevant trends and findings in the diagnosis and management of DMI.ConclusionsEarly recognition of DMI is key, so appropriate treatment can be initiated. MRI is the radiological study of choice. A combination of bed rest, glycemic control, and non-steroidal anti-inflammatory drug therapy appears to yield the shortest time to symptom resolution and the lowest risk of recurrence.

Autophagy degrades pathogens in vitro. The autophagy gene Atg5 has been reported to be required for IFN-γ-dependent host protection in vivo. However, these protective effects occur independently of autophagosome formation. Thus, the in vivo role of classic autophagy in protection conferred by adaptive immunity and how adaptive immunity triggers autophagy are incompletely understood. Employing biochemical, genetic and morphological studies, we found that CD40 upregulates the autophagy molecule Beclin 1 in microglia and triggers killing of Toxoplasma gondii dependent on the autophagy machinery. Infected CD40−/− mice failed to upregulate Beclin 1 in microglia/macrophages in vivo. Autophagy-deficient Beclin 1+/− mice, mice with deficiency of the autophagy protein Atg7 targeted to microglia/macrophages as well as CD40−/− mice exhibited impaired killing of T. gondii and were susceptible to cerebral and ocular toxoplasmosis. Susceptibility to toxoplasmosis occurred despite upregulation of IFN-γ, TNF-α and NOS2, preservation of IFN-γ-induced microglia/macrophage anti-T. gondii activity and the generation of anti-T. gondii T cell immunity. CD40 upregulated Beclin 1 and triggered killing of T. gondii by decreasing protein levels of p21, a molecule that degrades Beclin 1. These studies identified CD40-p21-Beclin 1 as a pathway by which adaptive immunity stimulates autophagy. In addition, they support that autophagy is a mechanism through which CD40-dependent immunity mediates in vivo protection and that the CD40-autophagic machinery is needed for host resistance despite IFN-γ.

oxygen species (ROS) production has recently been established as an essential contributor in the pathogenesis of obesity-associated insulin resistance. The FoxO1 pathway plays a role not only in nutrient sensing but also in regulating ROS production. We exposed adipocytes to free fatty acids (FFA) and demonstrated that FoxO1 protein levels decrease in a dose-dependent manner. The FoxO1 downregulation correlated with an increase in the production of ROS and a proinflammatory adipokine pattern characterized by a decrease in adiponectin and an increase in IL-6, plasminogen activator inhibitor-1, and monocyte chemotactic protein-1 mRNA expression levels. Similarly, a decrease in FoxO1 protein levels was seen in adipocytes of db/db mice compared with controls. Treatment with the sirtuin agonist resveratrol, which translocates FoxO1 to the nucleus, increased FoxO1 protein levels in adipocytes exposed to FFA. This correlated with a decrease in the generation of ROS and a partial reversal of the proinflammatory adipokine pattern. Together these results indicate that the insulin-resistant adipocyte produced by the exposure to a high concentration of fatty acids is characterized by decreased levels of FoxO1. These data also suggest that modulation of the Sirt1/FoxO1 pathway is a potentially useful therapeutic target for the obesity-induced dysfunctional adipocyte. inflammatory cytokines; insulin resistance; fatty acids OBESITY IS ASSOCIATED WITH insulin resistance and an increased risk for diabetes and cardiovascular disease (16,18). The strong association between obesity and insulin resistance implicates the adipocyte as an important link in the pathophysiology of these diseases. Adipose tissue from obese individuals show activation of inflammatory pathways, with the elaboration of cytokines such as monocyte chemotactic protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), and 22) contributing to the systemic inflammation characteristic of obesity. Free fatty acids (FFA) are likely important mediators of this response, in part through the activation of PKC and IB kinase ␤, each of which can activate inflammatory pathways and also inhibit insulin signaling (14,33).In addition to having an important role in the activation of inflammatory pathways, fatty acids are also implicated in the activation of oxidative stress, not only by uncoupling oxidative phosphorylation and increasing the generation of oxygen species but also by impairing endogenous antioxidant defenses (31). In diabetes, the increased flux of FFA increases mitochondrial reactive oxygen species (ROS) production, which in turn interferes with insulin signaling (15). If lipid oversupply is causally linked to the inflammatory response and to the generation of oxidative stress, it is reasonable to expect that approaches that have antioxidant and anti-inflammatory effects on adipocytes should have a beneficial effect on insulin sensitivity.The FoxO (forkhead member of the class O) family of forkhead transcription factors comprises three functionally related ...