Carraguard Vaginal Gel Safety in HIV-Positive Women and Men in South Africa

OBJECTIVE: To assess the safety of the candidate microbicide Carraguard gel in HIV-positive women and men. DESIGN: A randomized, placebo-controlled, triple-blinded clinical trial of Carraguard gel when applied vaginally once per day for 14 intermenstrual days by sexually abstinent and sexually active HIV-positive women; and when applied directly to the penis once per day for 7 days by sexually abstinent HIV-positive men. METHODS: In each cohort (n = 20 per cohort), participants were randomized to Carraguard, methylcellulose placebo, or no product (1:1:1). In addition to traditional microbicide trial safety endpoints, the effects of microbicide use on vaginal shedding of HIV-1 RNA and markers of genital inflammation, epithelial sloughing, and microhemorrhage were also explored. RESULTS: Gel compliance was high in both gel-use groups in the 3 cohorts. Carraguard use was not associated with abnormal genital findings, other abnormal clinical findings, markers of genital inflammation, epithelial sloughing or microhemorrhage, or self-reported symptoms in women and men, or with abnormal vaginal flora or genital shedding of HIV-1 RNA in women. Adverse events were mostly mild, not attributed to gel use, and similarly distributed between groups. CONCLUSIONS: Once-daily use of Carraguard for 7 to 14 days appeared to be safe in HIV-positive women and men.     

Safety Analysis of the Diaphragm in Combination with Lubricant or Acidifying Microbicide Gels: Effects on Markers of Inflammation and Innate Immunity in Cervicovaginal Fluid

Objective  Diaphragms are being considered for use with vaginal microbicide gels to provide enhanced protection against sexually transmitted pathogens. The purpose of this study was to determine whether use of a diaphragm with microbicide or placebo gel causes cervicovaginal inflammation or perturbations in cervicovaginal immune defense.
Method of study  Eighty-one non-pregnant women were randomized into three groups and instructed to use Milex^® (CooperSurgical, Inc., Trumbull, CT, USA)diaphragms overnight for 14 days in combination with one of the two acid-buffering microbicide gels [ACIDFORM^™ (Instead Inc., La Jolla, CA, USA) or BufferGel^™ (BG; ReProtect Inc., Baltimore, Maryland)] or placebo gel (K-Y Jelly^®; Personal Products Inc., Raritan, NJ, USA). Cervicovaginal lavages (CVLs) were performed prior to study entry and on days 8 and 16. Nine soluble mediators of vaginal inflammation or immune defense were measured in CVLs by Bio-Plex or ELISA.
Results  Use of diaphragms with placebo or microbicide gel was not associated with increased levels of inflammation markers. Concentrations of secretory leukocyte protease inhibitor (SLPI) were markedly reduced in the BG group.   Conclusion 

Daily use of a diaphragm with placebo or acidifying microbicide gel did not cause cervicovaginal inflammation. However, diaphragm/BG use was associated with markedly reduced levels of SLPI, an important mediator of innate immune defense. Further studies are warranted to establish the safety of diaphragm/microbicide gel combinations.     

Analysis of proinflammatory and anti-inflammatory cytokine serum concentrations in patients with multiple sclerosis by using a multiplexed immunoassay

We examined cytokines and other inflammatory markers in serum samples from 833 patients with multiple sclerosis and 117 healthy control subjects. A multiplexed immunoassay was used to assess the concentrations of 13 cytokines/inflammatory markers: interferon (IFN)-γ; interleukins (ILs)-1β, 2, 4, 5, 6, 8, 10, 12, and 13; tumor necrosis factor (TNF)-α; IL-2 receptor; and soluble CD40 ligand. Significant increases between patients and control subjects were found for IFN-γ (mean, 7.5 vs 0.4 pg/mL; P = .0002), IL-2 (mean 5.7 vs 1.0 pg/mL; P =.0002), IL-1β (mean, 23.0 vs 11.3 pg/mL; P ≤ .0001), TNF-α (mean, 4.1 vs 1.2 pg/mL; P = .01), IL-4 (mean, 1.4 vs 0.1 pg/mL; P ≤ .0001), IL-10 (mean, 16.8 vs 7.5 pg/mL; P = .03), and IL-13 (mean, 4.5 vs 0.8 pg/mL; P ≤ .0001). Profiling cytokines in multiple sclerosis may help to identify mechanisms involved in the pathogenesis of the disease, aid in monitoring the disease course and in evaluating responses to specific therapies, and, potentially, lead to new therapies directed at cytokines or their receptors.     

Interleukin-7 and immunologic failure despite treatment with highly active antiretroviral therapy in children perinatally infected with HIV-1

Baseline interleukin-7 (IL-7) level has been proposed as a predictor of immunologic response to antiviral therapy, and the use of exogenous IL-7 has been suggested in the treatment of HIV-infected patients. Therefore, we investigated the relationships between IL-7 serum levels and immunologic outcome of highly active antiretroviral therapy (HAART) in 24 children perinatally infected with HIV-1. IL-7 serum levels were evaluated by enzyme-linked immunosorbent assay before switching antiretroviral treatment from double therapy to HAART and then again after 12 weeks of HAART. Differences were analyzed between children with immunologic failure and those without. At baseline, IL-7 levels were significantly higher in HIV-1-infected children than in 24 healthy age-matched uninfected children (16.6 +/- 8.7 vs. 9.5 +/- 2.4 pg/mL, respectively; P < 0.001). IL-7 levels inversely correlated with CD4 T-lymphocyte percentage both at baseline (r = -0.71, P < 0.001) and after 12 weeks of HAART (r = -0.49, P = 0.01). We observed no correlation between IL-7 levels and viral load (r = 0.29, P = 0.17 at baseline; r = 0.30, P = 0.15 after 12 weeks). Baseline IL-7 levels were similar in HIV-1-infected children with or without subsequent immunologic failure (15.1 +/- 8.8 vs. 17.5 +/- 8.7 pg/mL, respectively; P = 0.75). After 12 weeks of HAART, IL-7 levels were 21.6 +/- 13.5 pg/mL in children with immunologic failure (P = 0.08 when compared with baseline levels) and 8.2 +/- 3.8 pg/mL in children without immunologic failure (P = 0.002 when compared with baseline levels). IL-7 levels were significantly higher (P = 0.003) in children with immunologic failure than in those without. Findings indicate that baseline IL-7 serum levels do not predict immunologic outcome of HAART and that immunologic failure occurs even in the presence of high IL-7 serum levels, thus suggesting no benefit from therapy with exogenous IL-7.     

Safety and acceptability of the candidate microbicide Carraguard in Thai Women: findings from a Phase II Clinical Trial

OBJECTIVE: To determine the safety and acceptability of vaginal application of Carraguard, a carrageenan-derived candidate microbicide gel. DESIGN: A randomized, placebo-controlled, triple-blinded clinical trial was conducted in Chiang Rai, northern Thailand. METHODS: Women were asked to insert one applicator of study gel vaginally at least three times per week (with or without sex) and to use gel with condoms every time they had sex. Safety was assessed by visual inspection of the vagina and cervix, changes in vaginal flora and self-reported symptoms at day 14, month 1 and then monthly for up to 1 year. Acceptability was assessed through reported use of the gel, return of used and unused applicators, and quarterly interviews. RESULTS: One hundred sixty-five women were randomized: 83 to Carraguard and 82 to the placebo (methylcellulose gel) group. Study gel use was similarly high in both groups throughout the trial with an average of four applicators per week. Carraguard use was not associated with abnormal genital clinical findings, abnormal vaginal flora, Pap smear abnormalities or other abnormal clinical signs or symptoms. Adverse events were mostly mild, not attributed to gel use, and similarly distributed between groups. Participants in both groups reported high acceptability. CONCLUSIONS: Carraguard can safely be used an average of four times per week with or without sex and is acceptable to Thai women. A Phase III efficacy trial of Carraguard is warranted and is currently ongoing in South Africa.     

A single nasal allergen challenge increases induced sputum inflammatory markers in non-asthmatic subjects with seasonal allergic rhinitis: correlation with plasma interleukin-5

BACKGROUND: Seasonal allergic rhinitis (SAR) is a risk factor for asthma in affected individuals. Nasal allergic inflammation enhances bone-marrow eosinophil production, mainly via IL-5, and rhinitis patients have increased airway inflammation during the pollen season. OBJECTIVE: To assess the impact of nasal allergy on sputum inflammatory markers. METHODS: In an open-labelled, randomized, placebo-controlled cross-over study with 16 non-asthmatic SAR patients (median age 25 years, 56% males), the effect of a single nasal allergen challenge performed out of season on induced sputum inflammatory parameters was evaluated. SAR patients were identified by history, skin-prick test and specific IgE. All patients had normal lung function/bronchial hyper-responsiveness out of season and a negative asthma/wheezing history. Sputum cells and supernatant levels of ECP, sICAM, IL-5 and IL-10, and plasma levels of IL-5 and ECP, were measured before and 24 h after nasal allergen challenge. After a washout period of at least 4 weeks, the procedure was repeated with placebo challenge (diluent). RESULTS: Nasal allergen challenge led to an increase in sputum ECP (pre = 60 +/- 12, post = 212 +/- 63 micro g/L, P = 0.02 vs. placebo), and sICAM (4.8 +/- 2.7 to 6.5 +/- 2.9 ng/mL, P = 0.02 vs. placebo), whereas IL-10 decreased after provocation (44 +/- 11 to 29 +/- 6 pg/mL, P = 0.06 vs. placebo). Sputum IL-5 was undetectable in all patients. The absolute number of blood and sputum eosinophils did not change significantly after allergen or placebo challenge (P > 0.07, both comparisons). Plasma levels of IL-5 increased after allergen challenge (8.7 +/- 2.9 to 14.5 +/- 3.9 pg/mL, P = 0.001), and the increase in plasma IL-5 was positively correlated with the rise in sputum ECP in a subgroup of 'responders' (n = 12, r = 0.71, P = 0.01). CONCLUSIONS: A single nasal allergen challenge in SAR patients increased markers of allergic inflammation in the lower respiratory tract, possibly via pronounced activation of inflammatory cells through circulating immediate-type reaction cytokines like IL-5. These findings may provide additional explanatory data for the high susceptibility of SAR patients to incident asthma.     

Acceptability of Carraguard, a candidate microbicide and methyl cellulose placebo vaginal gels among HIV-positive women and men in Durban, South Africa

Background and Methods  

When on the market, microbicides are likely to be used by individuals who do not know their HIV status. Hence, assessment of safety and acceptability among HIV positive men and women is important. Acceptability of Carraguard, the Population Council's lead microbicide candidate was assessed in a Phase I safety study among healthy HIV-positive sexually abstinent women and men, and sexually active women (20 per group), in Durban, South Africa. Participants were randomized to use Carraguard gel, placebo gel, or no product. All women in the gel arms applied 4 ml gel vaginally every evening for 14 intermenstrual days (women in the sexually active group inserted gel within 1 hour prior to sex on days when sex occurred), and sexually abstinent men applied gel directly to the penis every evening for 7 days. Acceptability was assessed by face-to-face structured questionnaires and semi-structured in-depth interviews with all participants. Gel use questions were applicable to participants in the gel arms only (13 sexually abstinent women, 14 sexually active women, and 13 abstinent men).     

A pilot study of high-adsorption hemofiltration in human septic shock

BACKGROUND: To compare the hemodynamic and biological effects of high-adsorption continuous veno-venous hemofiltration (CVVH) with standard CVVH in septic shock. METHODS: In a randomized cross-over clinical trial twelve patients with septic shock and multiple organ failure were enrolled at a tertiary intensive care unit. Patients were allocated to either 9 hours of high-adsorption hemofiltration (CVVH with 3 hourly filter change using AN69 hemofilters - 3FCVVH) or 9 hours of standard hemofiltration (CVVH without filter change - 1F-CVVH). RESULTS: Changes in hemodynamic variables, dose of noradrenaline required to maintain a mean arterial pressure greater than 75 mmHg and plasma concentrations of cytokines (IL-6, IL-8, IL-10 and IL-18) were measured. A 9-hour period of 3F-CVVH was associated with greater reduction in noradrenaline dose than a similar period of 1F-CVVH (median reduction: 16 vs. 3.5 microg/min, p=0.036; median percentage reduction: 48.1% vs. 17.5%, p=0.028). Unlike 1F-CVVH, 3F-CVVH was associated with a reduction in the plasma concentration of IL-6, IL-10 and IL-18 at 9 hours and a significant decrease 30 minutes after additional filter changes (IL-6: p<0.01, p<0.01; IL-10: p=0.03, p=0.016 and IL-18: p=0.016, p<0.01, respectively). Both, 3F-CVVH and 1F-CVVH were associated with decreased plasma concentrations of IL-8 at 9 hours (p<0.01, p<0.01, respectively). In a confirmatory ex-vivo experiment IL-6 concentrations substantially decreased during 3F-CVVH (at baseline 511 pg/mL and at end: 21 pg/mL) whereas IL-6 concentrations increased in control blood (at baseline 511 pg/mL and at end: 932 pg/mL). CONCLUSIONS: High-adsorption CVVH appears more effective than standard CVVH in decreasing noradrenaline requirements and plasma concentrations of cytokines in septic shock patients.     

Thrombopoietin and interleukin-6 levels in Henoch-Sch?nlein purpura.

BACKGROUND AND PURPOSE: Depending on the severity of the illness, thrombocytosis is found in about 60% to 70% of patients with Henoch-Sch?nlein purpura (HSP). Whether thrombocytosis is the result of an inflammatory reaction mediated by thrombopoietin (TPO) or other inflammatory cytokines such as interleukin (IL)-6 remains unknown. METHODS: Thirty two patients who met the diagnostic criteria for HSP were included. They were divided into two groups - HSP patients with thrombocytosis (n = 14) and those without thrombocytosis (n = 18) with a platelet count of 400,000/microL. Eight normal healthy controls were also included. TPO and IL-6 serum levels during the acute phase were measured by enzyme-linked immunosorbent assay. RESULTS: Patients with platelet counts greater than 400,000/microL in the acute stage had significantly lower TPO levels than patients with platelet counts lower than 400,000/microL (310 +/- 65.6 pg/mL vs 608 +/- 97.8 pg/mL, p=0.013). However, HSP patients with or without thrombocytosis had similar TPO levels as the healthy controls (441 +/- 176 pg/mL, p=0.89 and 0.29, respectively). IL-6 serum levels were significantly elevated in HSP patients during the acute stage of HSP (28.6 +/- 61.7 pg/mL vs 3.16 +/- 1.35 pg/mL, p=0.049). In patients with complications of glomerulonephritis or gastrointestinal hemorrhage (n = 12), IL-6 levels were significantly lower than in those without such complications (8.07 +/- 3.79 pg/mL vs 40.9 +/- 16.9 pg/mL, p=0.007). CONCLUSIONS: This study showed that thrombocytosis in HSP patients is a type of inflammatory reactive thrombocytosis, and that IL-6 may also play a role in the pathogenesis of HSP.     

Intravenous immunoglobulin treatment in women with recurrent abortions: increased cytokine levels and reduced Th1/Th2 lymphocyte ratio in peripheral blood

PROBLEM: The aim of this study was to investigate changes in peripheral blood Th1/Th2 cytokine levels and lymphocyte ratios after massive intravenous immunoglobulin (MIVIg) treatment for women with recurrent spontaneous abortion (RSA) of unexplained etiology. METHOD OF STUDY: Serum Th1 (IFN-gamma, TNF-alpha) and Th2 cytokine (IL-4, IL-10) levels were assessed by ELISA methods (n = 9) and peripheral blood Th1/Th2 lymphocyte ratios (n = 4) by flow cytometry before and after MIVIg treatments in women with four or more consecutive RSA. RESULTS: Pre-treatment serum IFN-gamma (0.06 +/- 0.09 pg/mL, mean +/- SD), TNF-alpha (0.21 +/- 0.45 pg/mL), IL-4 (0.70 +/- 1.16 pg/mL), and IL-10 (1.12 +/- 1.67 pg/mL) increased to 0.17 +/- 0.16 pg/mL, 0.77 +/- 0.28 pg/mL, 1.82 +/- 0.89 pg/mL, and 3.44 +/- 0.48 pg/mL, respectively, after MIVIg treatments (P < 0.05). CD4-positive IFN-gamma/IL-4 lymphocyte ratios (17.3 +/- 9.1) were reduced to 11.5 +/- 7.1 after treatment (P < 0.05). CONCLUSIONS: Massive intravenous immunoglobulin treatments increased peripheral blood cytokine levels and decreased Th1/Th2 lymphocyte ratios; thus, MIVIg treatments modify the peripheral Th1/Th2 balance.     

Increase in interleukin-6 following arterial injury is related to insulin resistance, the -174G-->C polymorphism and complex plaque morphology

Interleukin-6 (IL-6) is associated with many disease states in humans. We prospectively sought to determine whether IL-6 levels increased following percutaneous coronary intervention (PCI) in the absence of myonecrosis. Additionally, we systematically assessed other clinical and anatomic factors associated with IL-6 levels in a population of patients with coronary atherosclerosis undergoing PCI. Blood samples were collected from 117 patients at baseline, 8 and 16 h following PCI. Samples were assayed for IL-6, creatine kinase-myocardial band (CK-MB), troponin-I (Tn-I), high sensitivity C-reactive protein, glucose, haemoglobin A1c, and a lipid profile. Genotyping of the -174G-->C polymorphism of the IL-6 gene was performed. IL-6 levels increased following PCI among the study group (slope = 0.4 pg/mL/h, P = 0.001). IL-6 levels increased to a similar degree in the absence of myonecrosis. Patients with the XC genotype (either having the GC or the CC allele) had higher IL-6-values at baseline compared to GG genotype patients (4.9 +/- 6.4 vs. 2.6 +/- 1.8 pg/mL, P = 0.02). Multivariable predictors of detectable baseline IL-6 levels included XC genotype (odds ratio [OR]: 4.14, 95% CI 1.58-10.82, P = 0.004), ACC/AHA type C lesion classification (OR: 4.08, 95% CI 1.54-10.84, P = 0.005), elevated baseline Tn-I (OR: 3.31, 95% CI 1.16-9.43, P = 0.025), diabetes (OR: 3.00, 95% CI 1.11-8.09, P = 0.030), and waist circumference (OR: 1.49, 95% CI 1.08-2.06, P = 0.015). Predictors of peak IL-6 following PCI included the XC genotype (estimate 1.4, 95% CI 1.06-1.87, P = 0.019), homeostasis model assessment (estimate 0.99, 95% 0.982-0.999, P = 0.042) and baseline Tn-I > upper limit of normal (estimate 0.7, 95% CI 0.50-0.96, P = 0.039). Lastly, IL-6 increased following PCI even in the absence of myonecrosis as measured by Tn-I elevation. IL-6 levels are also related to the -174G-->C polymorphism, arterial injury, lesion complexity, and insulin resistance.     

白细胞介素-37在类风湿性关节炎患者血清表达水平的研究

目的 通过检测类风湿性关节炎(RA)患者血清中细胞因子白细胞介素(IL)-37、肿瘤坏死因子-α(TNF-α)、IL-18、炎性指标红细胞沉降率以及C-反应蛋白(C-reactionprotein,CRP)水平,观察RA患者临床数据包括压痛关节数,肿胀关节数以及DAS28评分等,探讨RA患者血清IL-37水平升高的意义以其在RA发病机制中可能的作用.方法 80例RA患者、80例健康对照患者,通过酶联免疫吸附试验(ELISA)法检测其血清中细胞因子水平.结果 RA患者血清中IL-37[(40.33±11.25)pg/mL]、TNF-α[(110.41 ±35.37) pg/mL]、IL-18[(121.73±29.22) pg/mL]水平以及红细胞沉降率(ESR)[(42.31±15.02) mm./h]、CRP[(38.31±17.22) mg/L]水平明显高于对照组IL-37[(18.21±5.72) pg/mL]、TNF-α[(30.19±6.82) pg/mL]、IL-18[(55.47±7.29) pg/mL]水平,组间差异有统计学意义(P＜0.05).IL-37的表达与TNF-α、IL-18水平呈正相关(相关系数r=0.981,P=0.001).结论 IL-37在RA患者体内高表达并与其它几种炎性因子的表达具有相关性,IL-37可能作为炎性抑制因子参与了RA的发生、发展.     

Increased levels of interleukin-15 in the peritoneal fluid of women with endometriosis: inverse correlation with stage and depth of invasion

BACKGROUND: Interleukin (IL)-15 is a novel cytokine with immunoregulatory and angiogenic properties. We compared IL-15 levels in the peritoneal fluid (PF) of women with and without endometriosis. METHODS: PF samples were obtained from 55 women with endometriosis (23 with superficial peritoneal implants, 19 with deep endometriotic implants and 13 with ovarian endometriomas). Eighteen women with normal pelvic anatomy undergoing tubal sterilization served as controls. RESULTS: PF IL-15 concentrations were increased in women with endometriosis (2.7 +/- 0.5 pg/ml) versus controls (2.1 +/- 0.3 pg/ml; P < 0.001). However, IL-15 levels were higher in women with superficial peritoneal implants (2.9 +/- 0.5 pg/ml) than women with deep endometriotic implants (2.6 +/- 0.4 pg/ml; P = 0.01) or ovarian endometriomas (2.2 +/- 0.4 pg/ml; P < 0.001). IL-15 was also higher in women with deep implants than in those with endometriomas (P < 0.05). PF IL-15 correlated inversely with both depth of invasion (r = -0.52) and the stage of endometriosis (r = -0.42). PF IL-15 levels demonstrated little variation during the menstrual cycle, and did not discriminate between women with infertility or pelvic pain. CONCLUSION: PF IL-15 levels are increased in women with endometriosis. However, IL-15 levels are inversely correlated with the depth of invasion and disease stage, suggesting a possible role for this cytokine in the early pathogenesis of endometriosis.     

Induction of inflammation as a possible mechanism of probiotic effect in atopic eczema-dermatitis syndrome

BACKGROUND: The immunomodulating mechanisms of Lactobacillus GG (LGG) and other probiotics are poorly understood. OBJECTIVE: We studied in vivo the immunologic effects of probiotics in infants with atopic eczema-dermatitis syndrome (AEDS) and cow's milk allergy (CMA). METHODS: Two hundred thirty infants with AEDS and suspected CMA received, concomitant with elimination diet, either LGG, a mixture of 4 probiotic strains (MIX), or placebo for 4 weeks. All available paired pretreatment and posttreatment plasma samples (n = 132) were analyzed for concentrations of IL-2, IL-4, IL-6, IL-10, TNF-alpha, IFN-gamma, soluble intercellular adhesion molecule 1, soluble E-selectin, TGF-beta1, TGF-beta2, and C-reactive protein. RESULTS: In infants with IgE-associated AEDS, treatment with LGG induced higher C-reactive protein levels than in the placebo group (geometric mean, 0.83 microg/mL [95% CI, 0.56-0.81] vs 0.42 microg/mL [95% CI, 0.27-0.65]; P = .021). Concomitantly, IL-6 levels increased after treatment with LGG ( P = .023) but not with MIX or placebo. Soluble E-selectin levels were higher after probiotic than after placebo treatment in infants with IgE-mediated CMA (LGG geometric mean, 86.7 ng/mL [95% CI, 75.2-100]; MIX geometric mean, 91.6 ng/mL [95% CI, 74.8-111.9]; and placebo geometric mean, 64.9 ng/mL [95% CI, 53-79.3]; analysis of covariance, P = .035; LGG vs placebo, P = .023; MIX vs placebo, P = .020). Use of MIX induced an increase in plasma IL-10 levels ( P = .016). CONCLUSION: Probiotics induced systemically detectable low-grade inflammation, which might explain the clinical effects of probiotics in AEDS and CMA.     

Plasma cytokines as predictors of coronary heart disease

BACKGROUND AND OBJECTIVE: Growing body of evidence explicitly suggests the significant role of inflammatory processes in vascular diseases related to atherosclerosis. Monocytes, present in every phase of atherogenesis, are the principal cells accumulating in atherosclerotic plaque. Monocyte Chemotactic Protein 1 (MCP-1) seems to influence firm adherence of rolling monocytes and infiltration into the artery wall. Although the significant meaning of inflammation in atherogenesis has been proved, potential role of antiinflammatory cytokines remains unknown. Interleukin 10 (IL-10) is a major cytokine of pleiotropic antiinflammatory function known to exert inhibitory effects on monocytes. Recent data emerging from clinical and pathological studies suggest important role of thrombosis and fibrinolytic disorders in atherosclerosis complications especially in coronary heart disease (CHD). Individuals with greater Plasminogen Activator Inhibitor 1 (PAI-1) level are believed to be more susceptible to cardiovascular disease. METHODS: In our study we measured the plasma levels of MCP-1, IL-10 and PAI-1 in 10 patients with stable angina and 10 healthy subjects. We also estimated its mutual correlations. The plasma levels of MCP-1, IL-10 and PAI-1 were determined with R&D kits (ELISA). RESULTS: Plasma levels of MCP-1 were significantly higher (261.5+/-40.7 pg/mL vs 73.3+/-3.05 pg/mL; p<0.0002) and also levels of PAI-1 were higher (79.36+/-5.8 ng/mL vs 35.88+/-1.38 ng/mL; p<0.0001) in patients with SA compared with the healthy control subjects. Whereas plasma levels of IL-10 were lower (11.6+/-0.5 pg/mL vs 16.5+/-0.4 pg/mL; p<0.0001) compared with control group and correlated with both MCP-1 plasma level (r=-0.67; p<0.0015) and PAI-1 concentration (r=-0.69; p<0.0008). CONCLUSION: The data obtained confirm the predictive role of cytokines in patients with stable coronary heart disease. The negative correlation of anti-inflammatory IL-10 and PAI-1 was also found.     

Interleukin-4 and interleukin-4 soluble receptor alpha levels in bronchoalveolar lavage from children with asthma.

BACKGROUND: In asthma there is increased expression of the Th2-type cytokine interleukin-4 (IL-4). IL-4 is important in immunoglobulin isotype switching to immunoglobulin E and adhesion of eosinophils to endothelium. OBJECTIVE: We hypothesized that levels of IL-4 in bronchoalveolar lavage (BAL) fluid would be increased in stable, atopic asthmatic children compared with controls and that levels of its physiologic inhibitor IL-4 soluble receptor alpha (IL-4sR alpha) would be correspondingly decreased. METHODS: One hundred sixteen children attending a children's hospital for elective surgery were recruited. A nonbronchoscopic BAL was performed, and IL-4 and IL-4sR alpha were measured in the BAL supernatants. RESULTS: There was no significant difference in IL-4 concentrations between atopic asthmatic children, atopic normal controls, and nonatopic normal controls [0.13 pg/mL (0.13 to 0.87) vs 0.13 pg/mL (0.13 to 0.41) vs 0.13 pg/mL (0.13 to 0.5), P = 0.65]. IL-4sR alpha levels were significantly increased in asthmatic patients compared with atopic controls [6.4 pg/mL (5.0 to 25.5) vs 5.0 pg/mL (5.0 to 9.9), P = 0.018], but not when compared with the nonatopic controls [5.2 pg/mL (5.0 to 10.6), P = 0.19]. CONCLUSIONS: Contrary to expectation, IL-4sR alpha levels are increased in BAL from stable asthmatic children compared with nonatopic controls, and we speculate that IL-4sR alpha is released by inflammatory cells in the airways to limit the proinflammatory effects of IL-4.     

High TNF-alpha and low IL-2 producing T cells characterize active disease in Takayasu's arteritis

We have investigated intracellular production by T cells and plasma levels of TNF-alpha, IL-2 and IFN-gamma in 12 active and 10 inactive Takayasu's arteritis (TA) patients and 12 healthy controls. The active TA compared to inactive TA and controls had higher TNF-alpha (52.7 +/- 22.3% vs. 32.9 +/- 14.2% and 35.2 +/- 14.5%, respectively; P = 0. 020), lower IL-2 (19.6 +/- 13.2% vs. 36.1 +/- 10.1% and 31.2 +/- 10.3%, respectively; P = 0.010) and comparable IFN-gamma (38.6 +/- 13.9% vs. 34.2 +/- 12.4% and 34.9 +/- 11.1%, respectively; P = 0.581) producing CD3+ T cells. There was no difference in the plasma levels of the cytokines between active TA, inactive TA and controls (TNF-alpha: 79.1 +/- 94.5 vs. 72.9 +/- 120.0 and 9.5 +/- 6.7 pg/ml, P = 0.110; IL-2: 4.3 +/- 4.8 vs. 6.6 +/- 4.7 and 8.6 +/- 4.5 pg/ml, P = 0.094 and IFN-gamma: 10.1 +/- 11.3 vs. 8.8 +/- 8.7 and 8.2 +/- 6.5 pg/ml, P = 0.871, respectively). The data show an important role of these high TNF-alpha and low IL-2 producing T cells in TA.     

Upregulation of Th1 cytokine profile (IL-12, IL-18) in bronchoalveolar lavage fluid in patients with pulmonary sarcoidosis.

Sarcoidosis, a systemic granulomatous disease of unknown etiology, is characterized by a predominantly Th1 cytokine milieu, which is involved in its immunopathogenesis. The role of novel immunologic markers reflecting T cell activity of the sarcoid immunologic response needs to be determined. The present study aims to evaluate the role of the Th1 cytokine pattern by estimating the local and systemic levels of interleukin-12 (IL-12) and IL-18 in bronchoalveolar lavage fluid (BALF), induced sputum, and serum of patients with pulmonary sarcoidosis. We studied prospectively 20 patients (12 women, 8 men) of median age 46 years (range 25-65) with sarcoidosis and 10 normal subjects (5 women, 5 men) of median age 39 years (range 26-60). IL-12 and IL-18 levels were measured using ELISA kits. The IL-12 BALF levels were significantly higher in sarcoidosis patients than in healthy subjects (5.64 +/- 0.21 pg/mL vs. 5.16 +/- 0.15 pg/mL, p < 0.001). In addition, IL-18 levels were significantly increased in BALF samples (47.69 +/- 6.29 pg/mL vs. 16.73 +/- 3.00 pg/mL, p < 0.001). A statistically significant decrease in IL-12 serum levels was detected in the sarcoid population compared with controls (5.77 +/- 0.50 pg/mL vs. 7.87 +/- 2.00 pg/mL, p < 0.001). No significant differences were detected in IL-12 and IL-18 levels between patients and controls in induced sputum samples. Our data suggest a potential role of IL-12 and IL-18 in the local immunologic response in pulmonary sarcoidosis. Further large-scale studies are needed to define the precise role of IL-12 and IL-18 in the immunopathogenesis of this disorder.     

Effect of histamine and adenosine 5'-monophosphate provocation on sputum neutrophils and related mediators in atopic patients.

BACKGROUND: Airway hyperresponsiveness and inflammation can be noninvasively studied by bronchial provocation using direct (histamine) or indirect (adenosine 5'-monophosphate [AMP]) stimuli and induced sputum. OBJECTIVE: To report on the immediate effects of histamine and AMP challenge on induced sputum neutrophil counts and related mediator levels. METHODS: We performed a single-masked, randomized, placebo-controlled, 3-way, crossover, methodological study in 14 atopic patients (median age, 25 years; 8 males; mean +/- SD forced expiratory volume in 1 second, 99% +/- 5%) without anti-inflammatory medication use. At baseline, sputum induction was performed. Bronchial challenges with AMP, histamine, or placebo were performed 48 hours later. Thirty minutes after challenge, sputum induction was performed again. Challenge periods in each patient were separated by more than 2 weeks. Sputum cells and the mediators leukotriene B4, interleukin 8, myeloperoxidase, and albumin were quantified. RESULTS: Comparing median challenge-induced relative changes in cells and mediators, neither histamine nor AMP challenge altered the induced sputum neutrophil counts (histamine, 2.7%; AMP, 2.95%; placebo, -2%; P > .07 for all), interleukin 8 levels (histamine, 2.4 ng/mL; AMP, -3.8 ng/mL; placebo, -0.2 ng/mL; P > .06), leukotriene B4 levels (histamine, -4.8 pg/mL; AMP, 3 pg/mL; placebo, 6 pg/mL; P > .08), or myeloperoxidase levels (histamine, 0.16 microg/mL; AMP, 0 microg/mL; placebo, -0.03 microg/mL; P > .07). Sputum albumin levels were increased after histamine challenge compared with AMP and placebo challenge (P < .01 for both). CONCLUSIONS: Histamine and AMP provocation have no major effects on induced neutrophil counts and related mediator levels in atopic patients, whereas histamine challenge induces plasma leakage. Potential interactions of noninvasive methods to evaluate airway reactivity and inflammation should be carefully considered.     

Increased cardiovascular disease risk indices in HIV-infected women

Little is known regarding cardiovascular disease risk indices in HIV-infected women. This study investigated cardiovascular disease risk indices in 100 consecutively recruited HIV-infected women and 75 healthy female control subjects. Subjects were recruited from hospital- and community-based health care providers. C-reactive protein (CRP), interleukin-6 (IL-6), adiponectin, lipid, and glucose levels were the main outcome measures. CT scan, dual-energy x-ray absorptiometry (DXA), and anthropometry were used to assess body composition. Although similar in age, weight, and racial composition, HIV-infected women demonstrated higher CRP (4.6 +/- 0.7 vs. 2.3 +/- 0.4 mg/L, P = 0.007), IL-6 (2.7 +/- 0.2 vs. 1.8 +/- 0.1 pg/mL, P = 0.02), triglyceride (1.84 +/- 0.21 vs. 0.85 +/- 0.05 mM, P = 0.0002), 2-hour glucose after oral glucose challenge (6.88 +/- 0.22 vs. 5.72 +/- 0.17 mM, P = 0.0003), and fasting insulin (81 +/- 8 vs. 45 +/- 2 pM, P = 0.0002) and lower high-density lipoprotein cholesterol (1.17 +/- 0.03 vs. 1.45 +/- 0.05 mM, P < 0.0001) and adiponectin (5.4 +/- 0.3 vs. 7.6 +/- 0.5 mg/L, P = 0.0001) levels compared with the control population. HIV-infected women had more abdominal visceral fat and less extremity fat by CT and DXA scan and demonstrated a higher waist-to-hip ratio (WHR) than the control population. Within the HIV group, CRP and other indices were significantly related to body composition in stepwise regression models. Among all subjects, WHR, but not HIV status, was significantly related to CRP and other cardiovascular disease risk indices. HIV-infected women demonstrate significantly increased risk factors for cardiovascular disease in association with abnormal fat distribution.