Gender, lifestyles, illness perception and stress in stable atrial fibrillation.

AIMS: The study is aimed at investigating if perceived stress in Stable Atrial Fibrillation (AF) has any gender-associated feature and relationships with lifestyle indicators and education level, and which relationship self efficacy, anxiety and depression and illness perception have, if any. PATIENTS AND METHODS: 88 consecutive patients referred for stable AF are studied by Psychological Stress Measure (PSM) test, Illness Perception Questionnaire (IPQ-R), Generalized Self-Efficacy scale (GSE) and Hospital Anxiety and Depression Scale (HADS). Mediterranean diet, physical activity increase and smoking withdrawal counseling were provided. RESULTS: AF patients have higher PSM associated with gender (women), older age, anxiety and depression. Higher GSE, greater Adherence to Mediterranean Diet profile and coffee habits (greater coffee users) are associated with a reduced hazard of perceived stress. By multiple linear regression, PSM is explained by Anxiety and IPQr (statistically significant are emotional representation and illness coherence subscales), which account for 92.2% of the variance (p<0.0001). CONCLUSION: Our results outline that psychological stress is greater in women in comparison with men. Illness perceptions are important in the context of perceived stress in AF. This effect appears to be modulated by greater self-efficacy and by Adherence to Mediterranean Diet profile, that when higher, are associated with a reduced hazard of perceived stress. We suggest that therapeutic interventions on illness perceptions can be warranted in order to achieve a lower psychological distress in AF patients.

Stress, abdominal obesity and intrarenal resistive index in essential hypertension.

AIM: Although it is commonly believed that a strong causal link exists between psychological stress and hypertension, as well with other factors, such as obesity, just what kind of empirical evidence supports this assumption is still controversial. The aim of the study is to investigate if perceived stress have any interference with intrarenal resistance and hence with mechanisms related to Essential Hypertension (EH) and if Anxiety, Depression, Self efficacy and Illness Perception can account for perceived stress. PATIENTS AND METHODS: Obesity, insulin resistance (HOMA), Doppler Renal Resistive Index (RRI) and glomerular filtration rate (GFR) are studied along with Psychological Stress Measure (PSM), Illness Perception Questionnaire (IPQ-R), Generalized Self-Efficacy scale (GSE) and Hospital Anxiety and Depression Scale (HADS) in 119 hypertensive patients referred for stable lasting EH, and 150 normal controls. Lower salt/lower calories Mediterranean diet, physical activity increase and smoking withdrawal counseling were provided. RESULTS: By Odds Ratios, higher risk of EH is associated with greater perceived stress, older age, lower GFR, obesity, greater RRI and insulin resistance. By Multiple Linear Regression the most significant variable that accounts for higher RRI are abdominal obesity and arterial pulse pressure; the only significant independent psychological variable that accounts for abdominal obesity are PSM and identity IPQ subscale. Self-Efficacy anxiety and Illness perception subscales (IPQr), accounts significantly for 62.0% of the variance to PSM, with possible effects on RRI and on the pathophysiological hypertension cascade. CONCLUSION: Worst identity and treatment control perceptions of EH, and a lower self-efficacy are the main psychological factors accounting for a greater stress. Interventions aimed to reduce perceived stress can be warranted in EH.

Pain assessment in fibromyalgia and rheumatoid arthritis: influence of physical activity and illness perception.

OBJECTIVE: Pain visual analog scales (VAS) have been validated for clinical use in fibromyalgia (FM) and rheumatoid arthritis (RA) patients. There are potential limitations, however, not only considering their use as a continuous measurement, but also with regard to the influence of personal illness perceptions, habitual physical activity and other life-style features. The aim of the study was to ascertain whether different illness perception, physical activity and clinical and laboratory characteristics can predict the severity of perceived pain assessed by VAS. MATERIALS AND METHODS: This is an observational comparative study of forty consecutive out-patients, 20 of them with fibromyalgia and 20 with rheumatoid arthritis, treated by medical and physical therapy. Patients were assessed also by Pain VAS, Health Assessment Questionnaire (HAQ) disability index, Ritchie index, Baecke questionnaire for physical activity, Illness Perception Questionnaire (IPQr) and SF36. RESULTS: Pain VAS is explained differently by some of the studied variables: in the total group HAQ and Ritchie index explain 29.8% of the variance; in the RA patients number of joints with pain and Ritchie index explain 52.7% of the variance; in FM patients total SF36 score and IPQr personal control dimension explains 44.7% of the variance. No definite role of anxiety and/or depression was found as predictor of perceived pain and disability. CONCLUSION: Pain perception and complaint are explained by belief in FM patients: This seems to suggest the need for a more articulated cognitive approach; addressing both diagnostic and therapeutic interventions to anxiety/depression issues is not supported by our results.

Human obesity relationship with Ad36 adenovirus and insulin resistance.

OBJECTIVES: Infection with specific pathogens may lead to increased adiposity: a specific adiposity-promoting effect of Ad36 human adenovirus, without the involvement of neurological mechanisms, was reported. The aim of this study is to investigate whether non-diabetic patients with earlier Ad36 infection show greater degrees of overweight obesity, of Insulin Resistance (IR), assessed by homoeostasis-model assessment (HOMA), and/or of other related factors. Moreover, the relationship, if any, among these factors and an earlier Ad36 infection, and the hypothesis of a mechanism involving IR are investigated. SUBJECTS: Ad36 seropositivity is assessed in 68 obese and 135 non-obese subjects, along with body composition, HOMA and laboratory investigations. RESULTS: Age, body mass index (BMI), waist-hip ratio, blood pressure, insulin, HOMA and triglycerides are significantly greater in the Ad36 seropositive group. Ad36 seropositivity, along with HOMA and total cholesterol, explains BMI variance. No Ad36 seropositivity effect to HOMA could be envisaged by the same statistical model. CONCLUSION: A significant association of Ad36 seropositivity with obesity and with essential hypertension in human beings is suggested by our study; this association is mostly significant in women. Our results do not support that any Ad36 adipogenic adenovirus effect is operating in human obesity through an insulin-resistance-related mechanism. Ad36 seropositive status could also be a hallmark of a clinical-metabolic profile possibly preceding obesity and diabetes in non-obese patients.

Insulin resistance in postmenopausal women: concurrent effects of hormone replacement therapy and coffee.

BACKGROUND: In postmenopausal women, an increase in insulin resistance is associated with an increased risk of diabetes, cardiovascular disease and breast cancer. Hormone replacement therapy (HRT) can reduce insulin resistance and coffee use is reported to decrease the incidence of diabetes. The aim of our study was to assess possible concurrent effects of HRT and espresso coffee intake on insulin resistance and on interdependent nutritional and clinical features. METHODS: A total of 478 healthy postmenopausal, non-diabetic women (aged 54.5 +/- 4.2 years) were studied: 360 had been on HRT for at least 2 years and 118 were not treated. Insulin resistance was assessed by a conventional homeostasis model (HOMA-IR). RESULTS: Insulin resistance is directly related to body mass index (p < 0.0001), and not with age and blood pressure; hypertensive menopausal women have a slightly higher body mass index but the same degree of insulin resistance as normotensive women. Women on HRT show lower insulin resistance, but not lower prevalence of arterial hypertension. Coffee use is associated with a decrease in insulin resistance in non-obese women receiving HRT, but not in other subsets. CONCLUSIONS: The combination of coffee consumption and HRT could lower insulin resistance in postmenopausal women. In overweight women, greater insulin sensitivity is associated with intake of espresso coffee and not with HRT; in normal weight women, only HRT is associated with lower insulin resistance.

Statistical assessment of functional categories of genes deregulated in pathological conditions by using microarray data.

MOTIVATION: A major challenge in current biomedical research is the identification of cellular processes deregulated in a given pathology through the analysis of gene expression profiles. To this end, predefined lists of genes, coding specific functions, are compared with a list of genes ordered according to their values of differential expression measured by suitable univariate statistics. RESULTS: We propose a statistically well-founded method for measuring the relevance of predefined lists of genes and for assessing their statistical significance starting from their raw expression levels as recorded on the microarray. We use prediction accuracy as a measure of relevance of the list. The rationale is that a functional category, coded through a list of genes, is perturbed in a given pathology if it is possible to correctly predict the occurrence of the disease in new subjects on the basis of the expression levels of the genes belonging to the list only. The accuracy is estimated with multiple random validation strategy and its statistical significance is assessed against a couple of null hypothesis, by using two independent permutation tests. The utility of the proposed methodology is illustrated by analyzing the relevance of Gene Ontology terms belonging to biological process category in colon and prostate cancer, by using three different microarray data sets and by comparing it with current approaches. AVAILABILITY: Source code for the algorithms is available from author upon request. SUPPLEMENTARY INFORMATION: Colon cancer data set and a complete description of experimental results are available at: ftp://bioftp:76bioftpxxx@marx.ba.issia.cnr.it/supp-info.htm.

Psychological stress measure in type 2 diabetes.

Psychological stress has been implicated as a cause of several psychosomatic disorders, but also as a factor that can unfavourably influence many diseases including diabetes mellitus. Measure of psychological stress in diabetes was performed by Psychological Stress Measure (PSM), a validated instrument, designed using 49 items drawn from descriptors generated by focus groups on stress. Clinical and psychological framework was assessed in a cohort of 100 type 2 diabetic patients (30 m, 70 f), aged 66.99 +/- 13.68 years considering disease grade, complications and level of instruction. Three other questionnaires were administered concurrently to all patients: Sickness Impact Profile (SIP), Functional Living Index (FLI) and SF-36 QOL. ANOVA statistical testing and Spearman correlation matrix were used also vs socio-cultural and clinical profile. Gender, obesity, diet compliance, smoking do not affect PSM response. Hypertensive patients and those with family history of diabetes show lower PSM scores, according to a sort of moderator effect on stress of concurrent and/or previous experience with chronic disease. Neuromuscular ailments are more prevalent in women; men vs women experience severe limitations of their working capacities and relational possibilities, with severe discomfort. In the whole, higher scores of PSM (greater stress p < 0.01) and lower scores of FLI (fair well-being perception; p < 0.01) are reciprocally related inside any school instruction level. Despite the great reciprocal association of the PSM vs FLI and SIP, no significant correlation is found between PSM vs SF-36 QOL. Socio-cultural elements interfere, and particularly instruction level quantified as school grades achieved, with the manner of living their disease. Interventions on psychological distress of type 2 diabetes mellitus patients is warranted, specially in the groups with lower levels of instruction which may need an attentive strategy for achieving a satisfactory coping with this disease.

[Quality of life in diabetes]. / Qualità della vita nel paziente diabetico.

Different clinical features of diabetic patients and type of complications are certainly a critical components of the global individual perception of quality of life (qol); but also personal socio-cultural characteristics interfere concurrently. Qol in diabetes was assessed considering disease grade, complications and level of instruction in a population of 100 diabetic patients (30 m, 70 f), aged 66.99 +/- 13.68 years. Two questionnaires were administered to all patients; Sickness Impact Profile (SIP) and Functional Living Index (FLI). SIP is an index of psycho-social, physical and motor functionality; FLI derives from a scale devised for cancer patients and adapted to diabetic patients. Both were analysed by Spearman correlation test, and assayed vs. sociocultural profile and clinical symptoms. Neuro-muscular ailments were more prevalent in women; men experience severe limitations of working capacities an relational possibilities, with severe discomfort. In the whole, higher scores of SIP (greater disability p: ns) and lower score for FLI (scant well-being perception r = 0.29: p<0.01) are related with lower school instruction level. Global QOL score is related as well with degree of instruction (r = 0.22: p<0.03). So QOL is altered during chronic diseases: however, in diabetes, qol impairment does not seem related with severity, treatment features and complications of diabetes. Socio-cultural elements, and particularly instruction level quantified as school grades achieved, interfere with the manner of living diabetic disease.

Perception of cultural correlates of medicine: a comparison between medical and non-medical students--the authoritarian health.

UNLABELLED: Aim of the study was to ascertain if a common cultural feeling of young people toward health, disease, physician's role and doctor-patient relationship, is present, and if under- and post-graduate students concepts and opinions modify during their stay in a School of Medicine. The study (1999-2001) was performed by anonymous questionnaires with 75 students (m = 28; f = 47) of the State School of Medicine, tested at the 3rd year, and with 73 students (m = 29; f = 44) tested at the 5th year of course; moreover with 71 (m = 30, f = 41) postgraduate residents at the 3rd year of specialty (Internal Medicine, Cardiology and Surgery). A group of 76 (m = 33; f = 43) students of the last year of a high school was also tested as reference group. RESULTS: Interference of medical under- and post-graduate school curricula on thoughts of youngsters toward health, disease, physician's role and doctor-patient relationship appears quite limited. Dissimilar way of thinking of medical vs. non-medical students was confined to some aspects concerning patient's possibility of healing, physician's role, behavior and function in chronic diseases. In the whole, our results suggest a trend, growing with the age of students, toward a more authoritarian and less "participative" approach with the patient: less confident relationship and more conflictual and antagonistic behaviors are widely considered and accepted. A general perspective with the construct of an authoritarian concept of health is superimposed as a net of rules and conditions on feelings' background of youngsters: postgraduate students regard themselves (and are perceived by younger students) as the guardians of an "healthy" system founded on scientific, economical and sociological grounds, as a work pointing to effectiveness, more than as a science with the target of efficacy. CONCLUSION: Impact of curricular studies of Medicine on youngsters is complex, but seems to modify only some and limited aspects of previously acquired thoughts and feelings on health and disease.

[Erythropoietin and cisplatin-induced neuropathies in cancer patients]. / Eritropoietina e neuropatie da cisplatino nei pazienti oncologici.

Anaemia commonly occurs in cancer patients on chemotherapy, often necessitating blood transfusion, and, in most recent years, treatment with human recombinant cythropoietin (rHuEPO). However, several extra-hematological effects were reported for EPO, and multi-organ physiological effects on development and repair of tissues are described both on nerves and muscles. Moreover, EPO is presently used in oncological patients with the goal of preventing or limiting anemia secondary to chemotherapy. Ten patients with advanced lung cancer and without neurological impairment assessed by Siegal score and without severe anemia, were studied. Patients (age 56.2 +/- 8.3 years) were random assigned to two groups of 5 patients each: the control group and the EPO treated group. In both groups, at the end of the study, hemoglobin concentration was not different (above 9 mg/dl). In EPO treated group neurological score was 4.00 +/- 1.87, significantly lower (p < 0.004) in comparison with untreated group (score 9.20 +/- 4.32). From these preliminary data we suggest that EPO treatment in cancer patients can exert also a limiting effect on cisplatin peripheral neurotoxicity.

Interferon alpha and alcohol augment nuclear regulatory factor-kappaB activation in HepG2 cells, and interferon alpha increases pro-inflammatory cytokine production.

BACKGROUND: The mechanisms for decreased therapeutic response to IFNalpha in chronic hepatitis C patients with alcohol are unknown. We investigated the hypothesis that IFNalpha and alcohol regulate cells both in the liver parenchyma and the immune system. METHODS: We used the hepatocellular carcinoma cells (HepG2) to determine if IFNalpha (500-10,000 U/ml) or ethanol (25-100 mM) modulates NF-kB activation alone or in combination with TNFalpha (0.1-20 microg/ml) as determined in electromobility gel shift assays. IkB levels were evaluated in the cytoplasmic extracts by western blot. Monocytes from normal donors were activated with LPS (1 microg/ml) in combination with IFNalpha or ethanol overnight and TNFalpha, IL-6, and IL-12 were measured in the supernatants. RESULTS: In HepG2 cells, both IFNalpha and acute alcohol treatment induced NF-kappaB activation and augmented TNFalpha-induced NF-kappaB binding. Pretreatment of HepG2 cells with IFNalpha resulted in the highest levels of NF-kappaB activation in response to TNFalpha or TNFalpha plus ethanol stimulation. Supershift experiments confirmed that the NF-kappaB dimer induced by TNFalpha and its combination with IFNalpha or ethanol contains RelA (p65) and involves rapid degradation of IkappaBalpha. Experiments using the proteasome inhibitor, MG132, revealed that augmentation of NF-kappaB by ethanol and IFNalpha is mediated via the proteasome pathway. We show that in normal monocytes, IFNalpha augments LPS-induced production of the inflammatory cytokines TNFalpha, IL-6, and IL-12 (p < 0.06) without further modulation by acute alcohol treatment. CONCLUSIONS: These results suggest that IFNalpha can increase HepG2 cell sensitivity to TNFalpha and ethanol-mediated activation. Augmentation of monocyte inflammatory cytokines, particularly of IL-12 production, by IFNalpha could be a key element of the antiviral response in chronic HCV. These results support the hypothesis that the therapeutic benefits of IFNalpha likely involve activation of both immune and parenchymal cells in the liver.

Reduced alloreactive T-cell activation after alcohol intake is due to impaired monocyte accessory cell function and correlates with elevated IL-10, IL-13, and decreased IFNgamma levels.

BACKGROUND: Immunosuppression associated with chronic alcohol use is characterized by reduced antigen-specific T-cell response and impaired delayed type hypersensitivity. Increasing evidence suggests in chronic alcohol consumption models that reduced antigen-specific T-cell proliferation is due to insufficient accessory cell function. Accessory cell function, a critical step in recognition of viral antigens, is reduced in chronic hepatitis C. The severity of hepatitis C is increased by alcohol consumption. Thus, we investigated the effects of alcohol consumption on accessory cell activity of monocytes in supporting alloreactive T-cell proliferation. METHODS: Alloreactive T-cell proliferation was evaluated in a one-way mixed lymphocyte reaction (MLR). Mononuclear cells were isolated by Ficoll density gradient and monocytes by adherence. Alcohol (0.8 g/kg body weight, an equivalent of approximately three drinks) was given to nonalcohol-consuming individuals and blood samples were collected before, 4 hr, or 18 hr after alcohol consumption. Alcohol in vitro was administered at concentrations of 25-100 mM. RESULTS: T-cell proliferation in MLR was significantly reduced in the presence of physiologically relevant concentrations of alcohol in vitro (25-100 mM ethanol) (p < 0.05). In vivo alcohol consumption also depressed proliferation in the MLR when stimulator cells were obtained 4 hr after alcohol consumption. MLR was not decreased, however, in the presence of alcohol-exposed responder cells and normal stimulator cells, suggesting that the accessory cell population and not T cells are affected by alcohol. Decreased accessory cell function was further evidenced by reduced superantigen-induced (SEB) but not mitogen-induced (PHA) T-cell proliferation in samples obtained 18 hr after alcohol intake (35% reduction). Reduced accessory cell function was not due to changes in surface expression of monocyte costimulatory molecules (HLA class I, HLA-DR, CD80, CD86, CD40). We found reduced IFNgamma, elevated IL-10, and unchanged IL-4 levels during T-cell proliferation in samples obtained 18 hr after alcohol consumption. Acute alcohol treatment resulted in increased IL-13 in the MLR. CONCLUSION: These data suggest that even on one occasion moderate alcohol intake can reduce allostimulatory T-cell activation via decreasing accessory cell function. Increased IL-10 and IL-13 plus the reduced IFNgamma production after acute alcohol use are likely to contribute to both the reduced T-cell proliferation and monocyte accessory cell function. These accessory cell mediated defects in T-cell activation may result in impaired antiviral and antitumor immunity after moderate acute alcohol use.

[Hydatidiform mole with coexistent fetus. Cytogenetic features, diagnosis, and management]. / Mola idatiforme con feto coesistente. Aspetti cito-genetici, diagnosi e management.

Hydatidiform mole with coexistent fetus is an unusual entity caused by two distinct types of pregnancy: the first one is a partial hydatidiform mole, while the second is a twin pregnancy in which a mole coexists with a normal fetus. In these two separate genetic entities, the counseling and the mother-fetus prognosis are different. Two cases of mole with coexistent fetus are reported: a partial hydatidiform mole typically tripliod and a partial mole with unusual diploid karyotype. Prenatal diagnosis is remarkable for the evaluation of fetus development related with his karyotype. Triplody excludes all hope of a non-malformed surviving child and termination of pregnancy is desirable, while normal karyotype the possibility of a continuation of pregnancy may be considered.

Inhibition of lipopolysaccharide-mediated NFkappaB activation by ethanol in human monocytes.

Alcohol use is typically associated with impaired immunity and increased host susceptibility to infection, partially due to decreased inflammatory response. Acute ethanol exposure has been shown to down-regulate monocyte production of inflammatory cytokines. Activation of the pluripotent transcription factor NFkappaB is a pivotal step in the induction of inflammatory cytokines, chemokines and growth factors. Therefore, we hypothesized that alcohol may alter NFkappaB activation, thus providing a mechanism for the decreased inflammatory cytokine production by monocytes after acute alcohol treatment. We show here for the first time that alcohol inhibits lipopolysaccharide (LPS)-induced NFkappaB activation in human monocytes by decreasing DNA binding of the p65/p50 heterodimer as seen in electrophoretic mobility shift and supershift assays. We also demonstrate that alcohol prevents LPS-induced nuclear translocation of p65 and to a lesser extent that of the p50 subunits. NFkappaB activation is regulated via phosphorylation and proteolytic degradation of IkappaB. Thus, we investigated the effect of acute ethanol treatment on IkappaB in human monocytes. Alcohol did not prevent LPS-induced IkappaBalpha degradation but decreased the levels of phospho-specific IkappaBalpha (Ser32). Finally, for the first time we show that de novo protein synthesis is necessary to bring about the ethanol-mediated inhibition of LPS-induced NFkappaB activation. Consequently, these results suggest that physiologically relevant concentrations of alcohol interfere with NFkappaB activation and thereby may affect the regulation of NFkappaB-controlled gene activation.

Body composition and long-term levo-carnitine supplementation.

PURPOSE: To evaluate the effect of long-term levocarnitine supplementation on nutritional state of patients in maintenance dialysis. PATIENTS AND METHODS: We studied by multifrequency-BIA (bioelectric impedance analysis) two groups of patients in maintenance bicarbonate hemodialysis for at least 4 years, comparable with respect to gender and age, and without liver disease, diabetes and malignancy. One group (25 patients) was treated with levocarnitine (1g/die) for three years or more; the control group (35 patients) never received this agent. RESULTS: Long-term levocarnitine supplementation was associated with higher serum levels of total protein and albumin in comparison to the control group. These effects were not associated with an increase in body fat mass and/or in total body water content, which are potentially detrimental conditions, especially considering the reported frequent association with circulatory and blood pressure alterations. CONCLUSIONS: Levocarnitine is able to improve the nutritional state, and this is associated with higher protein catabolism rate, i.e. with a higher protein intake, without detrimental effects on dialysis efficacy and adequacy.

Regulation of monocyte IL-12 production: augmentation by lymphocyte contact and acute ethanol treatment, inhibition by elevated intracellular cAMP.

IL-12, a monocyte-derived cytokine, is pivotal in activation of cellular immune response and inflammation. Both inflammatory response and cellular immunity are impaired by acute ethanol consumption. Here, we found that in vitro acute ethanol treatment (25-100 mM) results in a dose-dependent and significant increase of IL-12 in IFN-gamma (100 U/ml) plus Staphylococcal enterotoxin B (SEB; 1 microg/ml) stimulated monocytes and mononuclear cells but not in unstimulated cells from non-alcoholic blood donors. There was significantly greater IL-12 production in the MNC population compared to isolated Mphi (P < 0.001). Prevention of monocyte surface contact with either purified T lymphocytes or monocyte-depleted MNC resulted in a significant, 65+/-20%, decrease in IL-12 production regardless of IFN-gamma, SEB or ethanol stimulation suggesting that Mphi T-cell surface contact provides an additional signal for IL-12 production. In addition to cell surface contact, soluble mediators, particularly IL-10 and PGE2 may regulate IL-12 production. The cyclooxygenase inhibitor, Indomethacin (10(-6)M), augmented both IL-12 and IL-10 levels in isolated monocytes and mononuclear cells whether induced by medium, SEB or SEB plus 25 mM ethanol suggesting that regulation of IL-12 production via the cyclooxygenase pathway is independent of IL-10. Finally, elevation of intracellular cAMP levels by dbcAMP treatment consistently inhibited IL-12 as well as IL-10 production in monocytes induced by IFN-gamma or IFN-gamma plus 25 mM ethanol. These data suggest that augmentation of monocyte IL-12 by acute ethanol is not mediated via the cAMP pathway.

Regulation of monocyte interleukin-12 production by acute alcohol: a role for inhibition by interleukin-10.

Acute ethanol treatment results in decreased antigen presentation capacity (Th1-type immunity) and elevated interleukin IL-10 (Th2 cytokine) production in human monocytes. Monocytes can contribute to both Th1 (IL-12) and Th2 (IL-10) immune responses via production of IL-12 and IL-10, respectively. Thus, we tested the hypothesis that acute alcohol treatment might affect Th1/Th2 immune balance by altering monocyte production of IL-12 and IL-10. Neither acute ethanol treatment alone (25 to 100 mM) nor its combination with a bacterial challenge Staphylococcal enterotoxin B (SEB) induced IL-12 production in isolated blood monocytes. In contrast, the same physiological alcohol concentrations increased monocyte IL-10 levels, suggesting that ethanol can induce a dysbalance of monocyte-derived mediator production at the expense of Th1 cytokines. However, we found that monocyte activation with interferon-gamma (IFN-gamma) can prevent the preferential IL-10 induction by ethanol. IFN-gamma (100 units/ml) inhibited monocyte IL-10 production whether induced by 1 microg/ml of lipopolysaccharide (p < 0.01), 1 microg/ml of SEB (p < 0.02), or a combination of bacterial stimulation + ethanol (lipopolysaccharide: p < 0.01). Furthermore, decreased IL-10 was concomitant to an increase in IL-12 production in IFN-gamma-treated monocytes. Moreover, acute ethanol treatment augmented IL-12 production in IFN-gamma-treated monocytes in response to SEB stimulation (25 mM ethanol, p < 0.01; 100 mM ethanol, p < 0.01). Experiments with anti-IL-10 neutralizing antibody show that ethanol may prevent monocyte IL-12 induction via IL-10. These results suggest that inhibition of ethanol-induced IL-10 production by IFN-gamma treatment is permissive for IL-12 induction by alcohol stimulation in monocytes. Thus, our results imply that the presence or absence of IFN-gamma is critical in determining the effect of acute ethanol treatment on monocyte IL-12 versus IL-10 induction.

Alcohol-induced regulation of nuclear regulatory factor-kappa beta in human monocytes.

Acute ethanol exposure has the capacity to modulate immune functions, particularly, to down regulate monocyte production of inflammatory cytokines. However, the intracellular mechanisms for these effects of ethanol are yet to be understood. Considering that nuclear regulatory factor-kappa beta (NF-kappa B)/Rel is a common regulatory element of the promoter region of the inflammatory cytokine genes, herein, we tested the hypothesis that acute ethanol affects NF-kappa B activation in human monocytes. Adherence-isolated monocytes showed constitutive DNA binding activity of NF-kappa B. A clinically relevant dose (25 mM) of acute ethanol treatment in vitro increased NF-kappa B binding activity in monocytes with a preferential induction of the inhibitory, p50/p50, NF-kappa B/Rel homodimer, and resulted in no induction of the p65/p50 heterodimer. In contrast, lipopolysaccharide stimulation primarily induced the p65/p50 heterodimer that has been shown to result in gene activation. Thus, such unique activation of the inhibitory p50/p50 homodimer by acute ethanol treatment may result in inhibition rather than activation of NF-kappa B-regulated inflammatory cytokine genes. Consequently, these results suggest that physiologically relevant concentrations of ethanol may affect production of inflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 by disrupting NF-kappa B signaling in monocytes.