Inflammatory mediators in patients receiving long-term home parenteral nutrition.

This study was designed to examine circulating and urine cytokine levels in patients receiving long-term home total parenteral nutrition (TPN) support. Twelve patients who had been receiving home TPN for more than 1 year (range, 1.3-19.5 years) were enrolled for study. To avoid the potential confounding effects of intercurrent infection, patients were studied during periods of clinical stability without clinical evidence of infection. Ten normal healthy volunteers served as controls. Serum levels of albumin and C-reactive protein, temperature, body weight, and blood white cell counts were determined. The levels of soluble tumor necrosis factor receptor II (sTNF-RII) and interleukin 6 (IL-6) were measured in serum and 24-hr urine. The results showed that the concentrations of sTNF-RII and IL-6 in 24-hr urine and serum were significantly higher in patients, indicating that long-term home TPN may be associated with a persistent low-grade inflammatory state.

The systemic inflammatory response and its impact on iron nutriture in end-stage renal disease.

In most chronic disease conditions, the systemic inflammatory response and its mediators play an essential pathogenic role. Protein calorie malnutrition, a prominent feature of end-stage renal disease (ESRD), also develops, largely as a consequence of the systemic inflammatory response. ESRD (uremia), dialysis, systemic metabolic acidosis, and infections activate the systemic inflammatory response. Elevations in C-reactive protein and depressions of serum albumin below 4 g/dL are found in more than 50% of ESRD patients undergoing dialysis. In many patients receiving dialysis, the impact of this acute-phase response on measures of iron metabolism limits the ability to diagnose iron deficiency. Furthermore, there are risks to iron administration, although data linking iron overload to risk of infection in dialysis patients is suggestive, not definitive. It seems reasonable to hypothesize that the greatest risk of iron administration is in patents who are already infected, and the greater risk would be to raise the serum iron level and transferrin saturation precipitously. The total-dose infusion method, which provides all iron required to correct deficiency in 1 dose, is more likely to produce side effects and rapidly raise serum iron levels and transferrin saturation. The use of low-dose intravenous iron supplementation (10 to 20 mg per dialysis treatment or 100 mg every second week) avoids iron overtreatment and should reduce adverse events. In ESRD patients receiving dialysis, the importance of the systemic inflammatory response in the development of protein calorie malnutrition, the impact of the acute-phase response on iron nutriture, and the response to erythropoietin therapy must be considered to achieve an understanding of the altered responses to nutritional therapy in this setting.

Perioperative hyperglycemia, infection or risk?

This review covers the recent studies that have served to further our understanding of the nature of the relationship between perioperative hyperglycemia and nosocomial infection. On the one hand hyperglycemia can be a consequence of the systemic inflammatory response, and can serve as a marker of the severity of stress and the degree of immunocompetence resulting from infection or injury. Strong evidence is, however, emerging that hyperglycemia in the perioperative period can also be a significant risk factor for the development of nosocomial infection.

Induction of transcription factor interferon regulatory factor-1 by interferon-gamma (IFN gamma) and tumor necrosis factor-alpha (TNF alpha) in FRTL-5 cells.

While it is well known that interferon-gamma (IFN gamma) and tumor necrosis factor-alpha (TNF alpha) play a role in the regulation of thyroid growth and differentiated functions, the cellular and molecular mechanisms involved in mediating the effects of IFN gamma and TNF alpha on thyroid function are unknown. In the present study, we used FRTL-5 rat thyroid cells to examine the effects of IFN gamma and TNF alpha on gene expression of transcription factor interferon regulatory factor-1 (IRF-1), which is involved in mediating the effects of these cytokines in a number of cell types. Northern blot analysis of FRTL-5 mRNA showed a single IRF-1 mRNA at 2.2 Kb. In quiescent FRTL-5 cells, IRF-1 mRNA levels were low but detectable by Northern analysis. Incubation of FRTL-5 cells with IFN gamma or TNF alpha resulted in a dose- and time-dependent increase in IRF-1 mRNA levels. We have shown that TNF-alpha and IFN-gamma act synergistically to block the TSH-induced increase in type I 5'-deiodinase(5'D-I) activity and 5'D-I gene expression in FRTL-5 rat thyroid cells. Incubation of FRTL-5 cells with IFN gamma and TNF alpha in combination, however, did not synergistically increase IRF-1 mRNA levels. Electrophoretic mobility shift assay (EMSA) revealed that IFN gamma induced the formation of a single complex to a IFN gamma activation site (GAS) probe in a dose dependent manner. Several lines of evidence suggest that TNF alpha activates transcription factor nuclear factor-kappa B (NF kappa B) through activation of protein kinase C (PKC) or the hydrolysis of sphingomyelin to ceramide in a number of cell types. Here we demonstrate that hydrolysis of sphingomyelin to ceramide by sphingomyelinase (SMase), but not activation of PKC by 12-O-tetradecanoylphorbol 13-acetate (TPA), was involved in the activation of NF kappa B in FRTL-5 cells. Similarly, hydrolysis of sphingomyelin to ceramide, but not activation of PKC, resulted in an increased in IRF-1 mRNA levels in FRTL-5 cells. The present data demonstrate that IFN gamma and TNF alpha increase IRF-1 mRNA levels in FRTL-5 cells through activation of GAS and NF kappa B binding proteins, respectively. Thus, our results suggest that upregulation of IRF-1 may play a role in mediating the effects of IFN gamma and TNF alpha on thyroid function. Our results also suggest that the induction of IRF-1 mRNA by IFN gamma and TNF alpha is not the cellular mechanism involved in the synergistic effect of these cytokines on thyroid function.

Obesity and its comorbid conditions.

Obese patients are at an increased risk for developing many medical problems, including insulin resistance and type 2 diabetes mellitus, hypertension, dyslipidemia, cardiovascular disease, stroke, sleep apnea, gallbladder disease, hyperuricemia and gout, and osteoarthritis. Certain cancers are also associated with obesity, including colorectal and prostate cancer in men and endometrial, breast, and gallbladder cancer in women (1-6). Excess body weight is also associated with substantial increases in mortality from all causes, in particular, cardiovascular disease. More than 5% of the national health expenditure in the United States is directed at medical costs associated with obesity (7). In addition, certain psychologic problems, including binge-eating disorder and depression, are more common among obese persons than they are in the general population (8.9). Finally, obese individuals may suffer from social stigmatization and discrimination, and severely obese people may experience greater risk of impaired psychosocial and physical functioning, causing a negative impact on their quality of life (10).