Interleukin-6 (IL-6) expression and natural killer (NK) cell dysfunction and anergy in heart failure.

Immune dysfunction has been postulated to play a role in the pathophysiology of chronic heart failure. We examined the relation between interleukin-6 (IL-6) production and natural killer (NK) cell dysfunction in patients with chronic heart failure. Sera and peripheral blood mononuclear cells (PBMCs) were collected from 82 patients with advanced heart failure. Levels of circulating NK cells and T cells were determined by flow cytometry. NK cell function was measured by standard cytotoxicity assays. IL-6 in supernatants of PBMC cultured in vitro was quantitated by an enzyme-linked immunosorbent assay. The levels of circulating NK cells were lower in patients with heart failure than in normal controls (p = 0.0037). NK cells from patients with heart failure also exhibited impaired cytolytic functions in the absence of stimuli and in response to IL-2 and IL-12 (p <0.0001 for all conditions). PBMCs from patients with heart failure produced higher levels of IL-6 in response to a T-cell stimulus than did PBMCs from healthy controls (p = 0.0012). The level of IL-6 produced by unstimulated PBMCs in patients with heart failure correlated with NK cell cytolytic impairment (p = 0.0012). These results demonstrated that PBMCs are a source of IL-6 in patients with heart failure. Production of IL-6 by PBMCs correlated with NK cell anergy to other cytokines that use signal transduction pathways that may be regulated by IL-6. These results support a model of cytokine-induced anergy in conditions that result in high systemic levels of IL-6.

Beta blocker and angiotensin-converting enzyme inhibitor therapy is associated with decreased Th1/Th2 cytokine ratios and inflammatory cytokine production in patients with chronic heart failure.

OBJECTIVE: To examine the potential impact of beta-blockers and angiotensin-converting enzyme (ACE) inhibitors, medications which modulate beta-adrenergic signaling, on immune function in patients with chronic heart failure (HF). METHODS: 118 patients attending an HF center were tested for circulating levels of norepinephrine (NE), T cells and the inflammation-associated cytokine interleukin 6 (IL-6). Levels of the cytokines interferon-gamma (IFNgamma), IL-10, and tumor necrosis factor-alpha (TNFalpha) produced by cultured peripheral blood mononuclear cells (PBMC) were measured in culture supernatants following T cell stimulation in vitro. RESULTS: NE levels were significantly lower in patients receiving ACE inhibitors (p = 0.0263), with a trend toward lower NE in patients receiving beta-blockers. All patients exhibited relatively normal levels of T cells, and there was a trend toward higher levels of total (CD3+) and helper (CD4+) T cells (p = 0.0578 and 0.0932, respectively) in patients receiving either type of medication. The ratios of Th1 (IFNgamma) to Th2 (IL-10) cytokines were lower in patients receiving a combination of beta-blocker and ACE inhibitor therapy (p = 0.0373). NYHA class was a significant predictor of serum IL-6 (p < 0.0001). There was a trend toward lower levels of serum IL-6 in patients receiving both types of medications (p = 0.0606). TNFalpha production by CD3/CD28-stimulated PBMC was significantly lower in patients receiving ACE inhibitor medications (p = 0.0223). CONCLUSIONS: These results suggest that high sympathetic tone associated with chronic HF affects Th1/Th2 and inflammatory cytokine production, and that these effects can be modulated by medications. In addition to improvement in clinical parameters relating to cardiovascular function, beta-blocker and ACE inhibitor medications also appear to have a beneficial effect on the immune system in HF.

Acute dissociative responses in law enforcement officers involved in critical shooting incidents: the clinical and forensic implications.

The authors examine the prevalence of acute traumatic dissociative responses in a group of 115 law enforcement officers involved in critical incidents. Law enforcement officers were retrospectively surveyed for the presence of dissociative symptoms at the time of the critical incident, as well as for the presence of acute stress symptoms and posttraumatic stress symptoms. Results show that 90% of the officers reported experiencing a dissociative response during the critical incident. Thirty percent meet the Dissociative Criterion B of acute stress disorder under the DSM-IV. The mean number of dissociative symptoms in this group was two and one-half. In addition, 19% of the law enforcement officers reported varying forms of memory impairment for details of the incident. There were no reports of amnesia for the entire event. The clinical, forensic, and legal implications of these preliminary findings are discussed in this paper.

Estimates of nursing infant daily dose of fluoxetine through breast milk.

BACKGROUND: This study compared three methods of estimating the daily dose of fluoxetine to nursing infants and the relationship between these estimates and infant serum concentrations. METHODS: Breast milk and infant serum concentrations of fluoxetine and norfluoxetine were obtained from 10 nursing mother-infant pairs. Quantification of daily infant dose was determined by three methods: 1) collection of the total volume of breast milk over 24 hours and determination of the average breast milk concentration (Baby's Total Daily Dose); 2) determination of the maximum and minimum breast milk concentrations during 24 hours and an estimated milk consumption of 150 mL/kg/day (Atkinson Model); and 3) determination of the gradient of excretion of medication into breast milk at a specified time after the maternal dose, applying this gradient to each nursing collection and summing the values for 24 hours (Mathematical Model). The relationship between the 24-hour medication dose, obtained from each method, and the infant serum concentrations was examined. RESULTS: A total of 177 breast milk and 10 infant serum samples were collected. An estimate of the infant daily medication dose obtained by the Mathematical Model was the best predictor of total infant serum concentration. CONCLUSIONS: Breast milk analysis may allow one to determine whether medication concentrations will be detectable in an infant, eliminating the need for an infant serum concentration. Although the Mathematical Model seems to reflect infant serum concentration most accurately, all three methods suggest that the maximum dose that a nursing child receives over the course of a year equals as much as 120 mg, or 160 +/- 47% of the maternal daily dose.