Diabetes, aging, and their tissue complications.

The inactivation of NO by advanced glycation endproducts (AGEs), which accumulate on tissue proteins as a function of age and hyperglycemia, focused attention on the role of these ubiquitous posttranslational modifications in acquired impairments of vascular reactivity and other signaling processes. This observation occurred during a watershed period of basic and translational research in glycation that encompassed new pathologic phenomena and novel intervention strategies. How has the AGE paradigm for the tissue complications of aging and diabetes fared since the identification of the link between these glycation products and NO inactivation, and what lessons may be offered for future investigations?

Crosstalk between sentinel and helper macrophages permits neutrophil migration into infected uroepithelium.

The phagocytes of the innate immune system, macrophages and neutrophils, contribute to antibacterial defense, but their functional specialization and cooperation is unclear. Here, we report that three distinct phagocyte subsets play highly coordinated roles in bacterial urinary tract infection. Ly6C(-) macrophages acted as tissue-resident sentinels that attracted circulating neutrophils and Ly6C(+) macrophages.

Approaching the immunophysiology of steroid resistance.

Wang and colleagues have investigated a mechanistic basis for resistance to steroid therapy in systemic lupus erythematosus patients. Their examination reveals significant differences in macrophage migration inhibitory factor (MIF)-dependent expression of IκB, which is a critical cellular regulator of the broadly proinflammatory transcription factor NF-κB. Their studies also suggest that MIF may be a clinically useful biomarker in systemic lupus erythematosus and support the therapeutic targeting of MIF as a means to reduce clinical steroid resistance.

Distinct clinical and immunologic profiles in severe malarial anemia and cerebral malaria in Zambia.

Background: The mechanisms of severe malarial anemia and cerebral malaria, which are extreme manifestations of Plasmodium falciparum malaria, are not fully understood.

Methods: Children aged <6 years from southern Zambia presenting to the hospital with severe malarial anemia (n = 72), cerebral malaria (n = 28), or uncomplicated malaria (n = 66) were studied prospectively. Children with overlapping severe anemia and cerebral malaria were excluded.

MIF deficiency reduces chronic inflammation in white adipose tissue and impairs the development of insulin resistance, glucose intolerance, and associated atherosclerotic disease.

Chronic inflammation in white adipose tissue (WAT) is positively associated with obesity, insulin resistance (IR) and the development of type 2 diabetes. The proinflammatory cytokine MIF (macrophage migration inhibitory factor) is an essential, upstream component of the inflammatory cascade. This study examines whether MIF is required for the development of obesity, IR, glucose intolerance, and atherosclerosis in the LDL receptor-deficient (Ldlr(-/-)) mouse model of disease.

Series introduction: molecular and cellular basis of septic shock.

This series of overviews was contributed by participants of a Keystone Symposium, which was convened in early 2003 to address the topic of septic shock in an interdisciplinary manner. This occasion reflects a resurgence of interest in septic shock as a disease that may soon be approachable by new therapeutic interventions.