Obesity is an inflammatory disorder characterized by heightened activity of the innate immune system. Innate immune activation is central to the development of obesity-related insulin resistance; it also plays an important role in obesity-related tissue damage, such as that seen in atherosclerosis. Recent research has implicated the innate immune system in the pathophysiology of obesity-related liver disease. This review summarizes how innate immune processes, occurring both within and outside the liver, cause not only insulin resistance but also end-organ damage in the form of nonalcoholic fatty liver disease. (HEPATOLOGY 2008;48:670-678.)

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Controversy exists as to whether microscopic satellites influence prognosis or patterns of progressive disease in patients with clinical stage I melanoma. Fifty patients with clinical stage I melanoma and microscopic satellites were prospectively studied from 1972 to 1984. To allow for complete histopathology assessment, 30 patients with microscopic satellites who were prospectively seen from 1972 to 1979 were matched to a cohort of 77 patients with vertical growth-phase melanoma without microscopic satellites according to six attributes. The matched cohort study showed that the presence of microscopic satellites appeared to be associated with increased local regional cutaneous and regional nodal disease and a significantly decreased actuarial disease-free survival. A Cox multivariate regression analysis that involved 384 patients with vertical growth-phase clinical stage I melanoma showed that the presence of microscopic satellites independently predicted a poorer disease-free survival and overall survival. Therefore, this study demonstrated that the presence of microscopic satellites correlated with a significantly decreased survival.

Despite a 37% complication rate, a multidisciplinary team approach with adequate debridement, resection, and reconstruction can greatly improve QOL.

Protein-energy malnutrition induces immunosuppression that predisposes to sepsis, but the mechanisms are unclear. This study examines the role of the macrophage in host defense in the malnourished state. Swiss-Webster mice (N = 300) were randomly allocated to control (24% casein) or low-protein (2.5% casein) diets for 8 weeks. We studied the ability of two populations of macrophages, peritoneal macrophages, and Kupffer cells to produce superoxide anion after in vivo administration of endotoxin or mycobacterium (bacille Calmette-Guérin). Phorbol diester and Candida albicans were used as stimuli. In another group of mice, we evaluated the ability of interferon gamma to up-regulate superoxide anion release and Candida phagocytosis and killing. Mice under protein-energy malnutrition demonstrated decreased mean body weights, serum protein levels, and cell yields. Superoxide anion production in resident and activated (lipopolysaccharide, interferon gamma, bacille Calmette-Guérin infection) peritoneal macrophages was significantly reduced in the malnourished group. Candida phagocytosis and killing were also both depressed in malnourished mice. Kupffer cells failed to generate superoxide anion in all groups. We conclude that severe protein-energy malnutrition significantly impairs macrophage function, which could diminish response to acute and chronic septic challenges. Interferon gamma up regulated peritoneal macrophage and Kupffer cell microbicidal function, which suggests a therapeutic role for this lymphokine in the malnourished septic host.

Endotoxin (lipopolysaccharide [LPS])-induced cytokine release has been implicated in the pathogenesis of sepsis. Sublethal doses of LPS induce tolerance to a septic insult. This study evaluated pretreatment with interleukin 1 (IL-1) against an LPS challenge and examined its relationship to endotoxin tolerance. C3H/HeN mice (N = 100) were injected intraperitoneally with phosphate-buffered saline (control group), IL-1 (200 micrograms/kg), or LPS (1 mg/kg) for 3 days. On day 5, peritoneal macrophages were harvested and assayed for antimicrobial activity (superoxide anion production and Candida albicans phagocytosis). Serum cytokine levels and survival after an LPS challenge on day 5 were also assessed. Pretreatment with IL-1 or LPS significantly increased superoxide anion production, C albicans phagocytosis, and survival compared with pretreatment with phosphate-buffered solution. Interleukin 6 levels significantly decreased in the IL-1 and LPS groups. Peak levels of tumor necrosis factor significantly decreased only in the LPS group. Thus, pretreatment with IL-1 or low doses of LPS may exert protective effects by decreasing levels of interleukin 6 while increasing antimicrobial activity. Mice pretreated with IL-1 were protected from endotoxin despite elevated peak levels of tumor necrosis factor, suggesting a different mechanism for endotoxin tolerance than for tolerance to tumor necrosis factor.

Renal transplantation (RTx) is an effective therapy to improve clinical outcomes in pediatric patients with terminal chronic kidney disease. However, chronic immunosuppression with glucocorticoids (GCs) reduces bone growth and BMD. The mechanisms causing GC-induced growth impairment have not been fully clarified. Fibroblast growth factor 23 (FGF23) is a peptide hormone that regulates phosphate homeostasis and bone growth. In pathological conditions, FGF23 excess or abnormal FGF receptors (FGFR) activity leads to bone growth impairment. Experimental data indicate that FGF23 expression is induced by chronic GC exposure. Therefore, we hypothesize that GCs impair bone growth by increasing FGF23 expression, which has direct effects on bone growth plate. In a post hoc analysis of a multicentric randomized clinical trial of prepubertal RTx children treated with early GC withdrawal or chronic GC treatment, we observed that GC withdrawal was associated with improvement in longitudinal growth and BMD, and lower plasma FGF23 levels as compared with a chronic GC group. In prepubertal rats, GC-induced bone growth retardation correlated with increased plasma FGF23 and bone FGF23 expression. Additionally, GC treatment decreased FGFR1 expression whereas it increased FGFR3 expression in mouse tibia explants. The GC-induced bone growth impairment in tibiae explants was prevented by blockade of FGF23 receptors using either a pan-FGFR antagonist (PD173074), a C-terminal FGF23 peptide (FGF23180-205) which blocks the binding of FGF23 to the FGFR-Klotho complex or a specific FGFR3 antagonist (P3). Finally, local administration of PD173074 into the tibia growth plate ameliorated cartilage growth impairment in GC-treated rats. These results show that GC treatment partially reduces longitudinal bone growth via upregulation of FGF23 and FGFR3 expression, thus suggesting that the FGF23/Klotho/FGFR3 axis at the growth plate could be a potential therapeutic target for the management of GC-induced growth impairment in children.Intact plasma FGF23 levels were measured before RTx, and 1 week and 1 year after RTx ( Fig. 2A). Both groups had > 95% decrease in plasma FGF23 1 week after RTx, compared with baseline values, without differences between both groups. One year after RTx, SC patients had 3.2-fold higher plasma FGF23 levels compared with SW patients (1 year SC: 32.2 [24.0 to 45.7] pg/mL; 1 year SW: 10.1 [5.4 to 14.2] pg/mL; p < 0.001). When these FGF23 plasma levels were compared with a control group of healthy children ( Supplemental Table 3), SC patients had increased concentrations, but no significant differences compared with the ◼ 2 DELUCCHI ET AL. Fig. 4. Dexamethasone reduced growth of rat metatarsal explants, via fibroblast growth factor receptors (FGFRs). Prenatal rat metatarsal explants (extracted on E20) were cultured in the presence of dexamethasone (Dex; 1 nM); RU486 (RU; 25 μM), a glucocorticoid receptor antagonist; PD173074 (PD; 100 nM), a pan-FGFR antagonist; recombinant FGF23 (444 pM); or cell culture alone (Control), over ...

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