Skin test anergy in advanced heart failure secondary to either ischemic or idiopathic dilated cardiomyopathy.

Skin tests to recall antigens are performed as indicators of clinical outcomes in heart failure (HF). A diminution in the response to recall antigens, termed "anergy," is regarded as an indication of poorer clinical prognosis, although little analysis has been done to support that conclusion. Patients with advanced HF (n=222) in New York Heart Association classes III and IV, with complete datasets for all of the variables, were studied. The sample was 77% men, mean age 52+/-12 years, and left ventricular ejection fraction, 21+/-7. Patients with ischemic (n=113) and idiopathic (n=109) disease were analyzed separately. The relation of anergy to 1-year mortality and selected hemodynamic factors, blood chemistries, medications, and nutritional status markers was analyzed. Anergy was present in 45% (47% idiopathic and 42% ischemic) of patients. Anergy was related to 1-year mortality (univariate p=0.038) in patients with ischemic, but not idiopathic, HF. Anergic patients with ischemic HF had shorter survival times (p=0.035). Lower cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides were predictors (p <0.001) of mortality in idiopathic HF. In ischemic HF, lower cholesterol, LDL, and triglycerides were univariate predictors (p <0.001, p=0.004, and p=0.005, respectively) of skin test anergy, but not mortality. Thus, there were distinct differences in clinical correlates of skin test anergy in patients with idiopathic and ischemic HF. This study supports evaluation of anergy to skin tests as one of the markers of mortality in patients with ischemic HF.

Predictors of natural killer cell-mediated cytotoxicity deficiency in advanced heart failure secondary to either ischemic or idiopathic dilated cardiomyopathy.

The effect of psychologic variables (situational emotional state and psychiatric diagnosis) and physiologic variables (plasma norepinephrine, decreased cardiac exercise capacity, and elevated pulmonary capillary wedge pressure) on natural killer cell activity was evaluated in 19 patients with advanced heart failure of ischemic or idiopathic origin. Only peak exercise capacity was independently predictive of natural killer cell deficiency.

Differential regulation of IL-6 gene transcription and expression by IL-4 and IL-10 in human monocytic cell lines.

IL-4 and IL-10 inhibit the cytokine production and mRNA expression by monocytes/macrophages. To investigate the molecular mechanism of the inhibitory effect on transcriptional or post-transcriptional regulation of IL-6 gene expression by IL-4 and IL-10, we studied IL-6 production, expression level of IL-6 mRNA, IL-6 promoter activity, transcriptional activity of NF-kappaB and NF-IL-6, and IL-6 mRNA stability in human monocytic cell lines, THP-1 and U937, stimulated by PMA and LPS in the absence or the presence of IL-4 or IL-10. Both IL-4 and IL-10 were seen to inhibit IL-6 production and the expression of IL-6 mRNA in both monocytic cell lines studied. In chloramphenicol acetyltransferase assays, utilizing the transient transfection of a chloramphenicol acetyltransferase reporter plasmid containing the IL-6 gene promoter, IL-4, but not IL-10, suppressed the transcriptional activity of the IL-6 gene promoter stimulated by PMA and LPS. Electrophoretic mobility shift assays showed that IL-4, but not IL-10, inhibited nuclear NF-kappaB activity, and that IL-4 and IL-10 did not affect NF-IL-6 activity. On the other hand, IL-10 enhanced the degradation of IL-6 mRNA in a mRNA stability assay. These results suggest that IL-4 may inhibit the transcription of the IL-6 gene by affecting NF-kappaB binding activity, while IL-10 may inhibit the IL-6 mRNA levels post-transcriptionally, without suppressing promoter activity. Therefore, we conclude that IL-4 and IL-10 inhibit IL-6 production by different mechanisms in human monocytic cell lines.

Induction of IL-6 and IL-10 production by recombinant HIV-1 envelope glycoprotein 41 (gp41) in the THP-1 human monocytic cell line.

Elevated levels of circulating monokines (IL-6, IL-1, and TNF alpha) have been seen in HIV-1 infection, and the overproduction of these cytokines could contribute to AIDS pathogenesis in various ways. In previous work, we had seen that exposure of human monocytes to HIV-1, including inactivated, noninfectious HIV, led to rapid IL-6 gene expression and secretion. To investigate cytokine production in response to components of HIV by monocytes/macrophages, production of IL-6 and IL-10 were examined in a human monocytic cell line, THP-1, stimulated by HIV proteins. IL-6 production was induced in THP-1 cells by a detergent lysate of HIV, particularly fractions at molecular weight of 25-50 kDa. Recombinant HIV envelope glycoprotein 41 (gp41), but not gp120 or p24, also was seen to induce significant IL-6 production by THP-1 cells. These results suggest that gp41, transmembrane protein, is the primary HIV-encoded protein involved in inducing IL-6 production. IL-10 was also produced with delayed kinetics, following IL-6 production in THP-1 cells stimulated by gp41. To investigate a possible regulatory role for IL-10 in HIV-induced monokine production, recombinant IL-10 was added to gp41-exposed THP-1 cells. IL-10 inhibited gp41-induced IL-6 production and reduced the expression of IL-6 mRNA. When anti-human IL-10 neutralizing antibody was added to THP-1 cells, IL-6 production was enhanced. These results suggest that the IL-6 production may be downregulated by endogenously produced IL-10 and that IL-10 may downregulate cytokine production by HIV-activated monocytes via an autoregulatory mechanism.

Natural killer cell anergy to cytokine stimulants in a subgroup of patients with heart failure: relationship to norepinephrine.

Heart failure is a disease characterized by chronically high levels of plasma norepinephrine and anergy in the cytotoxicity of circulating natural killer (NK) lymphocytes. This study shows that NK anergy extends to a significantly reduced cytotoxicity in response to the powerful NK stimulants, interleukin (IL)-2 and interferon (IFN)-alpha. Fifteen patients with heart failure, New York Heart Association stage III or IV, were studied for NK-cell-mediated cytotoxicity. The patients were divided into two groups based upon their NK cytotoxicity function: (1) those who had minimal baseline cytotoxicity and failed to respond following stimulation by IL-2 and IFN-alpha (n = 6), and (2) those who were about at the level of normal controls, and were responsive to IL-2 and IFN-alpha (n = 9). There was no relationship between the anergy and the etiology of the heart failure, laboratory indicators of heart failure, serum albumin or sodium, state anxiety, age or sex of the subjects. There was a statistically significant negative correlation between the response of NK cells to the stimulators IL-2 and IFN-alpha and the level of plasma norepinephrine in the heart failure patients. This was corroborated by in vitro testing of direct effects of norepinephrine on normal NK cells, which indicated that baseline cytotoxicity and the ability of these cells to respond to IL-2 were inhibited in a dose-dependent manner. The findings indicate that the NK cell anergy seen in heart failure patients extends to the response to the stimulators IL-2 and IFN-alpha in a subgroup of patients.

Cadmium inhibits IL-6 production and IL-6 mRNA expression in a human monocytic cell line, THP-1.

Cadmium is a known immunotoxic agent in animal studies. Cells of the mononuclear phagocytic system are strategically located at portals of entry in humans and therefore may be particularly at risk for cadmium exposure through contaminated air, food, and drinking water. The purpose of this study was to determine whether there were changes in interleukin-6 (IL-6) production, a pleiotropic cytokine, when an activated human monocytic cell line was exposed to cadmium. Results suggest that there were statistically significant lower levels of IL-6 at 0.06 mM cadmium (P < 0.05), and 0.8 and 0.1 mM cadmium (P < 0.01), determined via the ELISA method. IL-6 messenger RNA (mRNA) levels were also decreased at these cadmium concentrations. The addition of a chelating agent, EDTA, to the cultures prevented the suppression of IL-6 secretion.

Evaluation of high-risk smoking practices used by the homeless.

The purpose of this study was to evaluate the prevalence of high-risk smoking practices in a homeless population. High-risk cigarette smoking practices include misuse of tobacco products or alternative methods of cigarette smoking that increase the likelihood of ingestion of toxic substances and infectious agents that can potentiate the hazards associated with cigarette smoking. An 84-item questionnaire was developed by the researcher to measure these practices. Fifty-six male and three female homeless people were interviewed in downtown Los Angeles. The most common high-risk smoking practices were cigarette sharing (86%); smoking cigarettes remade from discarded cigarette butts and filters (71%); smoking cigarettes remade by others (63%); smoking discarded cigarette butts (63%); blocking filter vents (24%); using things other than tobacco, such as discarded cigarette filters and drugs, in remaking cigarettes (22%); and smoking discarded cigarette filters (19%). These high-risk smoking practices pose a greater risk of exposure to toxins trapped in filters and tobacco remains and increase the threat of infectious disease transmission. The long-term effects of high-risk smoking practices among the homeless have potential economic implications for society.

Risk factors for disease in a homeless population.

Risk factors of smoking, drug and alcohol abuse, obesity, and sedentary lifestyle were related to health problems of clients at a walk-in clinic for the homeless. The sample of 1252 clients was predominately male (91.4%) and multiethnic, with a majority (65%) age 18 to 40 years. Data on diagnoses of health-related conditions were collected from clinic charts, coded into ICD categories, analyzed for relationships of risk factors to health problems, and compared with categories of diagnoses in a matched national sample of ambulatory care visits. Findings indicate that a larger proportion of homeless suffered from health problems in 24 of 27 diagnostic categories than the nonhomeless. Most prevalent were respiratory, dermal conditions, injuries, and digestive problems, in that order. Risk factors of alcohol abuse, smoking, sedentary lifestyle, drug abuse, and obesity were predictive of health problems in 18 of the categories analyzed. The findings suggest that immediate interventions such as education and rehabilitation to reduce risk factors, and provision of facilities for personal hygiene and cleaning of clothing could reduce some of the health-related conditions in this population while longer-term solutions of housing and employment are sought. The analysis model developed here appears to be a useful way of comparing relative effects of risk factors as a basis for establishing priorities for interventions.

Validity and reliability of the Pressure Sore Status Tool.

There is not yet a universal system for describing the status of pressure sores. The purpose of this study was to assess the validity and reliability of an instrument developed by the researchers for evaluation of pressure sores, the Pressure Sore Status Tool (PSST). This study was part of a larger study, which included development of a theoretical model for creation of items for the PSST. A nine-member expert judge panel established content validity of items on the instrument. Data were analyzed using a content of validity index (average index for tool = .91) and judges' comments were used to modify two items on the PSST. Two Enterostomal Therapy (ET) nurses independently used the revised tool to rate 20 pressure sores on ten adult medical-surgical patients, at two observation times. Interrater reliability was established at r = .91 for first observation and r = .92 for the second observation (p < .001). Intrarater reliability was r = .99 for rater one and r = .96 for rater two (p < .001). Future research will focus on refinement and further reliability testing of the instrument.

Differences in T cell receptor restriction fragment length polymorphisms in patients with rheumatoid arthritis.

OBJECTIVE: The purpose of this study was to determine whether a T cell receptor (TCR) polymorphism, either by itself or in combination with particular HLA polymorphism, leads to susceptibility to rheumatoid arthritis (RA). METHODS: Eight restriction fragment length polymorphisms (RFLPs) detected with TCR gene segments were investigated in 46 individuals with RA and were compared with data from normal control subjects. RESULTS: A statistically significant difference in the genotype frequencies of a Taq I RFLP detected with the TCR alpha constant region (C alpha) gene was noted. In addition, when the DR4+ subpopulations were examined, the allelic frequency of a 2-kb Bam HI fragment detected with a V beta 8 gene was increased in the samples from RA patients (P less than 0.0086). CONCLUSION: The results of this study suggest that germline differences in the TCR repertoire may be associated with RA, and that there is a contributory effect of DR4+ haplotypes with certain TCR haplotypes in susceptibility to RA.

Comparison of thermodilution and transthoracic electrical bioimpedance cardiac outputs.

Current methods of measuring cardiac output require the invasive insertion of a thermodilution catheter with its concomitant risks and complications. We examined the noninvasive method of transthoracic electrical bioimpedance (TEB) in comparison with thermodilution cardiac outputs in a sample of 44 critically ill patients with poor left ventricular function (left ventricular ejection fraction less than 30%) and with either ischemic or idiopathic dilated cardiomyopathy. Dyspnea, mitral regurgitation, tricuspid regurgitation, and difference between real and ideal weight had the most marked effects on the correlation between the two methods, with lesser influence by left ventricular ejection fraction, height, weight, hemoglobin, hematocrit, and aortic regurgitation. TEB and thermodilution cardiac outputs were correlated, at r = 0.51 (p less than 0.00009), but the low reliability and low percentage of TEB readings within 0.5 L/min of thermodilution cardiac outputs (31%) renders TEB inadequate for clinical measurement of cardiac outputs in this patient population.

In vitro reversibility of cadmium-induced inhibition of phagocytosis.

Cadmium chloride, administered chronically in the drinking water of CBA/H mice, produced a delayed clearance of particles and soluble material bearing Fc fragments (D. W. Knutson, D. L. Vredevoe, K. R. Aoki, and L. Levy, 1980, Immunology, 40, 17-26; D. L. Vredevoe, L. Levy, D. Knutson, G. Cook, and P. Cohen, 1985, Environ. Res. 37, 373-382). The inhibition was reversed upon removal of the cadmium from the water, even though a tissue load of cadmium persisted. An in vitro system was developed to analyze the mechanism of the inhibition. Binding and ingestion of sheep red blood cells (E) treated with IgG (for measurement of Fc receptor activity) or IgM and complement (C) (for measurement of complement receptor activity) were studied in resident and elicited murine peritoneal macrophages in vitro. Elicited macrophages provided the most definitive test system. With this system, there was significant inhibition of ingestion of E-IgG and E-IgMC. Binding of both types of erythrocytes was not inhibited, except at the highest concentration (10(-4) M) of CdCl2 at which binding of only E-IgMC was affected. These effects were reversible upon removal of cadmium. Migration of Fc and C receptors on the macrophage surface was not significantly affected by cadmium. In general, cadmium did not alter the expression or the binding of Fc or C receptors on macrophages. The mechanism for delayed clearance appears to be due to inhibited internalization of the particles. This is consistent with the interpretation that cadmium is a membrane active agent.