BACKGROUND

Chronic inflammation has been implicated in the development of airway dysplasia and lung cancer. It is unclear whether circulating biomarkers of inflammation could be used to predict progression of airway dysplasia.

OBJECTIVE

We determined whether circulating levels of C-reactive protein (CRP) or other inflammatory biomarkers could predict progression of bronchial dysplasia in smokers over 6 mo.

METHODS

The plasma levels of CRP, interleukins 6 and 8, and monocyte chemoattractant protein 1 were measured at baseline in 65 ex- and current smokers who had at least one site of bronchial dysplasia>> 1.2 mm in size. Additional bronchial biopsies were taken after 6 mo from the same sites where dysplastic lesions were discovered at baseline. Progressive dysplastic lesions were defined as worsening of the dysplastic lesion by at least two grades or development of new dysplastic lesions.

RESULTS

Half of the participants developed progressive dysplastic lesions after 6 mo. The baseline CRP levels in these participants were 64% higher than those without progressive disease (p = 0.027). Only one of eight (13%) participants with CRP < or = 0.5 mg/L developed progressive disease, whereas 31 of 57 (54%) participants with CRP>> 0.5 mg/L developed progressive disease (p = 0.011). The odds of developing progressive disease were 9.6-fold higher in the latter than in the former group.

CONCLUSIONS

Plasma CRP, in concert with lung function and pack-years of smoking, appears to have excellent predictive powers in identifying participants with bronchial dyplastic lesions whose lesions progress to more advanced stages of dysplasia.

OBJECTIVE

To establish a multiplex amplification refractory mutation system (ARMS) in fluid and dried whole blood, and to perform a pilot study to examine the role for single-nucleotide polymorphisms (SNPs) of inflammation-associated genes (interleukin [IL]-1 and -10, tumor necrosis factor-alpha [TNFA], and toll-like receptor-4 [TLR4]) and their interaction with clinical chorioamnionitis (CAM) in prematurity.

METHODS

We established a quadruplex ARMS to detect the four above SNPs. Fifty-four women delivered at gestational age less than 32 weeks and 83 healthy female volunteers were genotyped. We compared (1) mothers of preterm infants with volunteers, and (2) women delivered before 29 weeks' gestation (n = 29) with those delivered at 29 to 31 completed weeks (n = 25).

RESULTS

Multiplex ARMS is feasible using both fluid and dried whole blood. We found no overall differences in genotype and allele frequencies between mothers of preterm infants and volunteers. Among women who had a preterm delivery, those with both CAM and IL10(-1082)*G allele, the risk for delivery before 29 weeks was markedly increased (odds ratio [OR] 22, 95% confidence interval [CI] 2.5 - 191).

CONCLUSIONS

The presence of both CAM and IL10(-1082)*G might play a role in extreme preterm delivery less than 29 weeks.

OBJECTIVE

Helicobacter pylori (H. pylori) infection stimulates the production of interleukin (IL)-1 beta, a pro-inflammatory cytokine and suppressor of gastric acid secretion. As both inflammation and hypochlorhydria, which might facilitate proximal colonization of H. pylori and other bacterial species alike, have been implicated in gastric carcinogenesis, much attention has been directed to functional genetic polymorphisms that affect the production of IL-1 beta. The purpose of this study was to clarify the role of these polymorphisms.

METHODS

We analysed a population-based, case-control study in 5 Swedish counties and a hospital-based, case-control study conducted in 8 Swedish hospitals, with a total of 351 gastric cancer cases and 539 controls. The IL1B-31, IL1B-511 and IL1B+3954 biallelic polymorphisms were genotyped using pyrosequencing. The variable number of tandem repeats (VNTR) polymorphism of IL1-RN was analysed using polymerase chain reaction (PCR) followed by gel electrophoresis. Relative risks were estimated by odds ratios with 95% confidence intervals, derived from unconditional logistic regression.

RESULTS

The risk of gastric cancer was unrelated to genotype in all of the studied polymorphic loci, and the absence of any association was confirmed in both the population-based and hospital-based case-control studies. Analyses confined to histological subtypes (intestinal or diffuse) and site-specific tumours (cardia or distal stomach), as well as analyses stratified by H. pylori infection status and family history of gastric cancer, did not reveal any significant increases or decreases in risk.

CONCLUSIONS

Our results do not lend support to the hypothesis that human genetic polymorphisms related to the production of IL-1 beta are associated with the risk of gastric cancer.

BACKGROUND

Obesity has been associated with increased incidence of colorectal cancer. Adipose tissue dysfunction accompanied with alterations in the release of adipocytokines has been proposed to contribute to cancer pathogenesis and progression. The aim of this study was to analyze plasma concentrations of several adipose tissue expressed hormones in colorectal cancer patients (CRC) and morbidly obese (MO) patients and to compare these concentrations to clinicopathological parameters.

METHODS

Plasma concentrations of adiponectin, resistin, leptin, active plasminogen activator inhibitor (PAI)-1, monocyte chemotactic protein (MCP)-1, <em>interleukin</em> (IL)-1 alpha, and tumor necrosis factor (TNF)-alpha were determined in 67 patients operated on for CRC (<em>31</em> rectal cancers, 36 colon cancers), 37 patients operated on for morbid obesity and 60 healthy blood donors (BD).

RESULTS

Compared to BD, leptin concentrations were lowered in CRC patients whereas those of MO patients were elevated. Adiponectin concentrations were only lowered in MO patients. Concentrations of MCP-1, PAI-1, and IL-1 alpha were elevated in both CRC and MO patients, while resistin and TNF-alpha were similarly expressed in MO and CRC patients compared to BD. Resistin concentrations positively correlated with tumor staging (p<0.002) and grading (p=0.015) of rectal tumor patients.

CONCLUSIONS

The results suggest that both MO and CRC have low-grade inflammation as part of their etiology.

OBJECTIVE

We propose that Crohn disease (CD) decreases bone formation via circulating inflammatory mediators. We therefore examined the effects of serum from newly diagnosed, untreated children with CD on osteoblasts in culture and the role of interleukin-6 (IL-6), a cytokine present in excess in active CD that also has direct effects on bone.

METHODS

Bone mineral density was measured by dual x-ray absorptiometry. Primary cultures of rat osteoblasts were treated with serum from patients with CD and healthy controls. We measured expression of osteoblast proliferation, viability, differentiation markers, and mineralized nodule formation. Neutralizing antibodies were used to inhibit the effects of IL-6 present in serum.

RESULTS

We studied 24 children with CD (14 male) and 31 controls (15 male). Spine bone mineral density was lower in patients with CD (Z score, -0.8 +/- 0.9 vs. 0.0 +/- 1.0 for controls; P < 0.05). Nodule formation was markedly decreased in osteoblasts treated with CD serum. However, CD serum did not affect osteoblast proliferation or viability. Expression of proteins characteristic of mature osteoblasts-osteocalcin and alkaline phosphatase-was reduced. Unlike our results in a model of intact bone, neutralization of IL-6 did not inhibit the effects of CD serum. Addition of IL-6 to control serum to match serum concentrations in CD had no effect either.

CONCLUSIONS

CD serum affects osteoblast function and probably differentiation in vitro, suggesting a mechanism by which CD may affect bone formation. IL-6 by itself is not sufficient to cause these effects and probably needs a cofactor present in intact bone.

In addition to a constitutive cyclo-oxygenase (Cox-1), human endothelial cells also possess an inducible cyclo-oxygenase (Cox-2) which plays an important role in the regulation of the synthesis of prostacyclin (prostaglandin I2). Cox-2 is regulated and expressed in large quantities upon activation of the cells by inducers such as phorbol myristate acetate (PMA), an activator of protein kinase C (PKC), or <em>interleukin</em>-1 alpha. We have investigated the involvement of protein tyrosine kinases in Cox-2 expression by human endothelial cells upon activation by these inducers. PMA or <em>interleukin</em>-1 alpha provoke an increase in the phosphorylation of substrates of 110 and 120 kDa and additional phosphorylations for a broad band of multiple substrates in the 70 kDa range. This stimulation was accompanied by the induction of Cox-2 protein, detectable after stimulation for 1 h, which is consistent with an increase in activity reflected by prostacyclin synthesis; no variation in the expression of Cox-1 could be observed. Three distinct inhibitors of protein tyrosine kinases, genistein, herbimycin or AG-213, reduced tyrosine phosphorylation of cell substrates, consistently with their pharmacological effects. Under these conditions, there was selective reduction of Cox-2 expression without modification of Cox-1. Regulation of Cox-2 induction is also dependent on the activation of PKC since Ro <em>31</em>-8220 or PKC depletion by PMA prevented its induction. Our results suggest that within the time-frame of our experiments these effects on kinases are specific for Cox-2 rather than Cox-1.

BACKGROUND

Eosinophilic airway inflammation is the hallmark of asthma, but it has also been reported in other conditions such as allergic rhinitis. We have tested whether the analysis of cells and chemicals in sputum can distinguish between patients with mild allergic asthma, those with allergic rhinitis, and healthy controls. The relationship between inflammation markers in sputum and nonspecific bronchial hyperresponsiveness to methacholine (BHR) (PD20 and maximal response plateau [MRP] values) was also evaluated.

METHODS

We selected <em>31</em> mild asthmatics and 15 rhinitis patients sensitized to house-dust mite. As a control group, we studied 10 healthy subjects. Every subject underwent the methacholine bronchial provocation test (M-BPT) and sputum induction. Blood eosinophils and serum ECP levels were measured. Sputum cell differentials were assessed, and eosinophil cationic protein (ECP), tryptase, albumin, and <em>interleukin</em> (IL)-5 levels were measured in the entire sputum supernatant.

RESULTS

Blood eosinophils and serum ECP levels were higher in asthma patients and rhinitis than in healthy controls, but no difference between asthma patients and rhinitis patients was found. Asthmatics had higher eosinophil counts and higher ECP and tryptase levels in sputum than rhinitis patients or control subjects. Sputum albumin levels were higher in asthmatics than in controls. Rhinitis patients exhibited higher sputum eosinophils than healthy controls. An association between sputum eosinophil numbers and MPR values (r= -0.57) was detected, and a trend toward correlation between sputum ECP levels and PD20 values (r= -0.47) was found in the rhinitis group, but not in asthmatics. No correlation between blood eosinophilic inflammation and lung functional indices was found.

CONCLUSIONS

Induced sputum is an accurate method to study bronchial inflammation, allowing one to distinguish between rhinitis patients and mildly asthmatic patients. The fact that no relationship was detected between sputum inflammation and BHR suggests that other factors, such as airway remodeling, may be at least partly responsible for BHR in asthma.

BACKGROUND

Atrial fibrillation (AF) might be associated with an inflammatory activation and reduced left ventricular (LV) function. Less is known with regard to newly introduced markers of LV dysfunction such as carbohydrate antigen-125 (CA-125) in subjects with AF. The aim of this study was therefore to assess possible associations between AF, inflammatory markers and CA-125.

RESULTS

Forty-eight consecutive patients with AF and 58 control patients in sinus rhythm were enrolled in this study. Patients with acute heart failure, chronic inflammatory or neoplastic disease were excluded from the study. Circulating levels of hs-C-reactive protein (CRP), <em>interleukin</em>-8 (IL-8), IL-6, soluble IL-2 receptor (sIL-2r), TNF-α and CA-125 were assessed; all patients underwent clinical examination with NYHA class assessment and echocardiography. Patients with AF were characterised by higher levels of IL-8 (180 ± 266 vs. 39 ± 43 pg/mL, P < 0·001), sIL-2r (987 ± 1045 vs. 680 ± 336 U/mL, P < 0·05) and TNF-α (26 ± 25 vs. 9 ± 4 pg/mL, P < 0·001). Patients with AF duration < 6 months had higher levels of CRP (54 ± 73 vs. 12 ± 14 mg/dL, P < 0·05) and IL-8 (251 ± 225 vs. 99 ± 123 pg/mL, P < 0·05) when compared with AF duration>> 6 months. CA-125 levels were not statistically different if comparing subjects with AF with controls and AF>> 6 months with AF < 6 months. Among patients with AF, CA-125 levels were significantly related to NYHA class, (r = 0·33, P < 0·05) as well as IL-6 levels (r = 0·<em>31</em>, P < 0·05). Results remained statistically significant even after multivariable correction for age, gender and LV ejection fraction.

CONCLUSIONS

AF is characterised by an inflammatory activation. Impaired functional class in AF subjects might be associated with increased CA-125 levels and higher inflammatory markers.

Ingesting carbohydrate (CHO) beverages during prolonged, continuous heavy exercise results in smaller changes in the plasma concentrations of several cytokines and attenuates a decline in neutrophil function. In contrast, ingesting CHO during prolonged intermittent exercise appears to have negligible influence on these responses, probably due to the overall moderate intensity of these intermittent exercise protocols. Therefore, we examine the effect of CHO ingestion on plasma <em>interleukin</em>-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and lipopolysaccharide (LPS)-stimulated neutrophil degranulation responses to high-intensity intermittent running. Six trained male soccer players performed 2 exercise trials, 7 days apart, in a randomized, counterbalanced design. On each occasion, they completed six 15-min periods of intermittent running consisting of maximal sprinting interspersed with less intense periods of running and walking. Subjects consumed either CHO or artificially sweetened placebo (PLA) beverages immediately before and at 15-min intervals during the exercise. At 30 min post-exercise, CHO versus PLA was associated with a higher plasma glucose concentration (p < .01), a lower plasma cortisol and IL-6 concentration (p < .02), and fewer numbers of circulating neutrophils (p < .05). Following the exercise, LPS-stimulated elastase release per neutrophil fell <em>31</em>% below baseline values on the PLA trial (p = .06) compared with 17% on the CHO trial (p = .30). Plasma TNF-alpha concentration increased following the exercise (main effect of time, p < .001) but was not affected by CHO. These data indicate that CHO ingestion attenuates changes in plasma IL-6 concentration, neutrophil trafficking, and LPS-stimulated neutrophil degranulation in response to intermittent exercise that involves bouts of very high intensity exercise.

Cardiac surgery with cardiopulmonary bypass triggers an inflammatory response involving proinflammatory cytokines such as tumor necrosis factor-alpha, <em>interleukin</em>-6, and <em>interleukin</em>-8. To elucidate the pathophysiology of this cytokine response, we explored the possible differences in cytokine responses between patients undergoing heart transplantation and those undergoing coronary artery bypass grafting. Plasma levels of tumor necrosis factor-alpha, <em>interleukin</em>-6, <em>interleukin</em>-8, and <em>interleukin</em>-10 were measured in eight patients undergoing heart transplantation (mean age 44 years) and eight patients undergoing coronary artery bypass grafting (mean age 61 years). Duration of cardiopulmonary bypass and ischemic time were both longer in the heart transplantation group than in the coronary artery bypass grafting group (133 +/- 26 min vs 100 +/- <em>31</em> min, p < 0.05, and 130 +/- 47 min vs 58 +/- 21 min, p < 0.005, respectively). Samples were collected before heparin administration, at aortic crossclamping and declamping, and at 0.5, 1, 1.5, 2, 4, 12, and 24 hours after declamping. Tumor necrosis factor-alpha levels were significantly higher 30 minutes after aortic declamping in the heart transplantation group than in the coronary artery bypass grafting group (68 +/- 30 vs 18 +/- 5 pg/ml, p < 0.05). <em>Interleukin</em>-6 and <em>interleukin</em>-8 levels were also significantly higher 90 minutes after declamping in patients undergoing heart transplantation than in those undergoing coronary artery bypass grafting (<em>31</em>0 +/- 63 vs 169 +/- 24 pg/ml, p < 0.05, and 73 +/- 17 vs 24 +/- 5 pg/ml, p < 0.01, respectively). Furthermore, <em>interleukin</em>-6 and <em>interleukin</em>-8 values 90 minutes after declamping were significantly correlated with the ischemic time (r = 0.72 and r = 0.82, respectively, both p < 0.05). <em>Interleukin</em>-10 levels in both groups rose to reach a peak value of around 115 pg/ml 1 hour after declamping. Patients undergoing heart transplantation exhibited a second peak of tumor necrosis factor-alpha, <em>interleukin</em>-8, and <em>interleukin</em>-10 levels 12 hours after declamping, probably related to the administration of rabbit antihuman thymocyte immunoglobulin (Thymoglobuline) 3 hours after declamping. <em>Interleukin</em>-6 levels decreased more significantly 12 and 24 hours after declamping in patients undergoing heart transplantation, probably related to methylprednisolone therapy. In conclusion, cardiopulmonary bypass is associated with the production of both proinflammatory and antiinflammatory cytokines. The production of proinflammatory cytokines in patients undergoing heart transplantation is higher than that in patients undergoing coronary artery bypass grafting, and this increase could be related to the longer duration of ischemia in the former group. The later course of cytokine levels after heart transplantation may be further influenced by immunosuppressive therapy.

BACKGROUND

The single-breath N(2) test (sbN(2)-test) is closely related to small airways pathology in resected lung specimens of smokers. We investigated whether uneven ventilation and airway closure are associated with specific markers of airway inflammation as obtained by bronchial biopsies, BAL, and induced sputum in patients with manifest COPD.

METHODS

Fifty-one patients with stable COPD not receiving corticosteroids were examined in a cross-sectional study (43 men; mean [SD] age, 63 +/- 8 years; exsmokers and smokers; median pack-years, 41 [interquartile range, <em>31</em> to 51 pack-years]). Postbronchodilator spirometry (FEV(1), 63 +/- 8% of predicted) and sbN(2)-test (slope of phase III [DeltaN(2)], closing capacity [CC]/total lung capacity [TLC] percentage of predicted) were performed. Inflammatory cell counts were assessed in bronchial biopsies, BAL (only in the first half of patients), and induced sputum. Neutrophil elastase (NE), secretory leukocyte proteinase inhibitor (SLPI), and <em>interleukin</em>-8 levels were determined in BAL fluid.

RESULTS

DeltaN(2) increased with subepithelial neutrophil numbers in bronchial biopsies (rs = 0.337, p = 0.017) and with NE levels (rs = 0.443, p = 0.039), NE/neutrophil ratio (rs = 0.575, p = 0.005) and SLPI levels (rs = 0.484, p = 0.022) in BAL. CC/TLC was associated with BAL neutrophil numbers (rs = 0.448, p = 0.048). The sbN(2)-test was not associated with any other inflammatory cell type in BAL or biopsies, nor with inflammatory cell counts in sputum. Of importance, the correlations between DeltaN(2) and BAL NE/neutrophil ratio, and between CC/TLC and BAL neutrophil numbers remained significant when adjusting for FEV(1) percentage of predicted.

CONCLUSIONS

The results of the sbN(2)-test are associated with neutrophilic inflammation in bronchial biopsies and BAL in patients with COPD. Our findings support a role of neutrophilic inflammation in the pathogenesis of small airways dysfunction in COPD.

BACKGROUND

The pharmacokinetics and immunodynamics of basiliximab were assessed in 39 pediatric de novo kidney allograft recipients to rationally chose a dose regimen for this age group.

METHODS

In study part 1, patients were given 12 mg/m(2) of basiliximab by bolus intravenous injection before surgery and on day 4. An interim pharmacokinetic evaluation supported a fixed-dose approach for study part 2 in which infants and children received two 10-mg doses and adolescents received two 20-mg doses. Blood samples were collected over a 12-week period for analysis of basiliximab and soluble interleukin-2 receptor concentrations, flow cytometry, and screening for anti-idiotype antibodies.

RESULTS

Basiliximab clearance in infants and children (n=25) was reduced by approximately half compared with adults from a previous study and was independent of age (1-11 years), weight (9-37 kg), and body surface area (0.44-1.20 m(2) ). Clearance in adolescents (12-16 years, n=14) approached or reached adult values. CD25-saturating basiliximab concentrations were maintained for 31+/-12 days in study part 1 with mg/m(2) dosing and for 36+/-14 days in study part 2 based on the fixed-dose regimen ( P=0.31). A single patient experienced a rejection episode during CD25 saturation. The duration of CD25 saturation in patients who experienced a rejection episode after desaturation did not differ from those who remained rejection-free for the full 6-month period: 34+/-6 days (n=6) vs. 35+/-14 days (n=33 patients); P=0.74. Anti-idiotype antibodies were detected in two patients; however, this did not influence the clearance of basiliximab or the duration of CD25 saturation.

CONCLUSIONS

To achieve similar basiliximab exposure as is efficacious in adults, pediatric patients <35 kg should receive two 10-mg doses and those>> or =35 kg should receive two 20-mg doses of basiliximab by intravenous infusion or bolus injection. The first dose is given before surgery and the second on day 4 after transplantation.

Acupuncture regulates inflammation process and growth factors by increasing blood circulation in affected areas. In this study, we examined whether acupuncture has an effect on wound healing in injured rat. Rats were assigned randomly into two groups: control group and acupuncture group. Acupuncture treatment was carried out at 8 sites around the wounded area. We analyzed the wound area, inflammatory cytokines, proliferation of resident cells, and angiogenesis and induction of extracelluar matrix remodeling. At 7 days after-wounding the wound size in acupuncture-treat group was decreased more significantly compared to control group. In addition, the protein levels of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and <em>interleukin</em>-1β (IL-1β) were significantly decreased compared to the control at 2 and 7 days post-wounding. Also, we analyzed newly generated cells by performing immunostaining for PCNA and using several phenotype markers such as CD-<em>31</em>, α-SMA, and collagen type I. In acupuncture-treated group, PCNA-positive cell was increased and PCNA labeled CD-<em>31</em>-positive vessels, α-SMA- and collagen type I-positive fibroblastic cells, were increased compared to the control group at 7 days post-wounding. These results suggest that acupuncture may improve wound healing through decreasing pro-inflammatory response, increasing cell proliferation and angiogenesis, and inducing extracellular matrix remodeling.

OBJECTIVE

We performed a phase I trial to determine whether in vivo expansion of activated CD4+ T cells was possible in cancer patients. 111Indium labeling was used to observe trafficking patterns of the infused stimulated CD4+ T cells. The influence of cyclophosphamide (CTX) dosing on immunologic outcome was also examined.

METHODS

Patients with advanced solid tumors or non-Hodgkin's lymphoma received CTX at 300 or 1,000 mg/m2 intravenously (i.v.). Leukapheresis was performed to harvest peripheral-blood mononuclear cells (PBMCs) either just before the CTX dose, or when the patient was either entering or recovering from the leukocyte nadir induced by CTX. An enriched population of CD4+ T cells was obtained by negative selection. The CD4+ T cells were activated ex vivo with anti-CD3, cultured with interleukin-2 (IL-2) for 4 days, and adoptively transferred. After adoptive transfer, patients received IL-2 (9.0 x 10(6) IU/m2/d) by continuous infusion for 7 days.

RESULTS

The absolute number of CD4+, CD4+/DR+, and CD4+/CD45RO+ T cells increased in a statistically significant fashion in all cohorts after the first course of therapy. The degree of CD4 expansion was much greater than CD8 expansion, which resulted in a CD4:CD8 ratio that increased in 26 of 31 patients. The greatest in vivo CD4 expansion occurred when cells were harvested as patients entered the CTX-induced nadir. One complete response (CR), two partial responses (PRs), and eight minor responses were observed. Trafficking of 111Indium-labeled CD4 cells to subcutaneous melanoma deposits was also documented.

CONCLUSIONS

CD4+ T cells can be expanded in vivo in cancer patients, which results in increased CD4:CD8 ratios. The timing of pheresis in relation to CTX administration influences the degree of CD4 expansion. Tumor responses with this regimen were observed in a variety of tumors, including melanoma and non-Hodgkin's lymphoma; a high percentage of patients had at least some tumor regression from the regimen that produced the greatest CD4+ T-cell expansion.

BACKGROUND

The goals of the present work were to study the embryotoxic effects of peritoneal fluid (PF) in women with or without endometriosis, and to relate any embryotoxicity to the severity of endometriosis, infertility or achievement of pregnancy, cytokine concentrations and lymphocyte populations.

METHODS

Sixty-six consecutive women of reproductive age, 54 with endometriosis (21 infertile) and 12 infertile without endometriosis, and another 12 fertile women as control group, were included in this study. They all underwent laparoscopy or laparotomy in the second half of the cycle, and PF was collected from the pouch of Douglas. The embryotoxicity of the PF was assessed by means of a mouse embryo assay, and expressed as the number of embryos that did not reach blastocyst stage. Cytokines and lymphocyte populations present in PF were also studied and correlated with embryotoxicity.

RESULTS

PF embryotoxicity was increased in women with endometriosis, but there was little correlation with the severity of the disease. However, although a clear relationship to the presence of infertility was not found, embryotoxicity appeared to be lower in those infertile patients with endometriosis who later became pregnant. We found a significant increase in embryotoxicity in the presence of high cytokine concentrations, especially with <em>interleukin</em>-6, and less so with <em>interleukin</em>-8 (P < 0.05). No good correlation was observed with lymphocyte populations, but CD56 (NK) cells were significantly increased in the PF of women with endometriosis. In general, the correlations for embryotoxicity were better when PF was diluted at 20% (91.4 +/- 17 versus 68.1 +/- <em>31</em>, P < 0.01).

CONCLUSIONS

These results suggest that alteration in the production of cytokines in the PF, especially IL-6, besides contributing to the endometriosis and its evolution, probably increases embryotoxicity. However, no correlation was found between the latter and associated infertility.

OBJECTIVE

Physical activity is effective in primary and secondary prevention of cardiovascular disease. In this study, we tested the hypothesis that exercise training improves glucose and lipid metabolism, the inflammatory/anti-inflammatory balance, and the outcome of elective percutaneous coronary intervention (PCI) in patients with stable coronary disease.

METHODS

Sixty-two patients scheduled to undergo PCI for stable angina were randomized to intensive physical activity (n=33) consisting of home-based exercise on a bicycle ergometer or maintain their usual sedentary life (n=29). The training program started 2 months before PCI and terminated 6 months afterwards. Clinical examination, blood sampling (fasting glucose, glycated hemoglobin, lipid profile, apolipoprotein B, apolipoprotein A1, C-reactive protein, serum amyloid A, interleukin-6, interleukin-8, and interleukin-10), and maximal exercise tests were performed at inclusion, 1 week before PCI, and 3 and 6 months afterwards.

RESULTS

Fifty-six patients [28 per group, 45 men, mean age 63 (SD 7.8) years] completed the follow-up. According to self-reports, patients in the training group exercised more often and longer [4.9 (SD 1.1) vs. 0.6 (SD 1.3) days/week, 36 (SD 12) vs. 15 (SD 31) min/session, P<0.0001]. Improvement in maximal exercise capacity was significantly better in the training group [27 (SD 27) vs. 9 (SD 27) W, P=0.02]. Exercise had no significant effects on glucose and lipid metabolism, plasma cytokines, or acute-phase reactants.

CONCLUSIONS

A home-based training program significantly improved maximal exercise capacity but did not affect glucose or lipid metabolism or markers of inflammation.

OBJECTIVE

To identify significant covariates in addition to spirometry that predict mortality in elderly subjects with obstructive airway disease (OAD).

METHODS

Two hundred sixty-eight (268) participants with OAD from the Health, Aging and Body Composition study, a community-based observational cohort of well-functioning elderly aged 70-79 years, were followed on average for 6.1 years. Covariates related to pulmonary and physical function, comorbidity, demographics, and three inflammatory markers (<em>interleukin</em>-6, tumor necrosis factor-alpha, C-reactive protein) were evaluated for their association with all-cause mortality (<em>31</em>%) by means of Kaplan Meier analysis and Cox proportional hazards modeling.

RESULTS

Percent predicted forced expiratory volume in one second (PPFEV1; hazard ratio [HR] = 2.03, p < 0.0001), knee extensor strength (HR = 1.36, p = 0.0002), interleukin-6 (HR = 1.37, p = 0.0002) and 400 m corridor walk time (HR = 1.24, p = 0.008) significantly predicted mortality. A multidimensional index, the PILE score, was constructed from PPFEV(1), interleukin-6, and knee extensor strength. Each one-point increase in PILE score (range: 1-10) was associated with a 30% increase in mortality (95% confidence interval: 0.16-0.47) after adjusting for age, race, gender, smoking, and comorbidity, resulting in a 10.4-fold higher risk of death between the highest and lowest risk category.

CONCLUSIONS

Subjects with OAD have a wide gradient of risk for mortality that can potentially be incorporated in clinical decision making.

Purpose: Cytokine storm, an uncontrolled overproduction of inflammatory cytokines contributing to an aberrant systemic inflammatory response, is a major pathological feature of acute respiratory distress syndromes being severe manifestations of COVID-19, thus highlighting its potential as a biomarker and therapeutic target for COVID-19. We aimed to determine associations of circulating levels of inflammatory cytokines with severity and mortality of COVID-19 by systematic review and meta-analysis.

<strong class="sub-title"> Methods: </strong> A comprehensive literature search in electronic databases consisting of PubMed, Scopus, and Cochrane Library and in a hand searching of reference lists from inception to July <em>31</em>, 2020, was performed using the following search terms: COVID-19, <em>interleukin</em> (IL)-6, IL-10, and tumor necrosis factor-alpha (TNF-α). Mean difference (MD) from individual studies was pooled using a random-effects model. Quality assessment, publication bias, meta-regression, subgroup, and sensitivity analyses were performed.

Results: A total of 6212 COVID-19 patients from 24 eligible studies were included. Compared with non-severe COVID-19 patients, systemic levels of IL-6 and IL-10, but not TNF-α, were significantly elevated in severe COVID-19 patients (MD = 18.63, 95% CI: 10.91, 26.35, P < 0.00001; MD = 2.61, 95% CI: 2.00, 2.32, P < 0.00001; respectively). For COVID-19 mortality, circulating levels of IL-6, IL-10, and TNF-α were found to be significantly increased in non-survivors when compared with survivors (MD = 57.82, 95% CI: 10.04, 105.59, P = 0.02; MD = 4.94, 95% CI: 3.89, 6.00, P < 0.00001; MD = 5.60, 95% CI: 4.03, 7.17, P < 0.00001; respectively).

Conclusion: Circulating levels of IL-6 and IL-10 might have great potential as biomarkers for the disease severity and mortality in COVID-19 patients.

Keywords: COVID-19; cytokine storm; interleukin-10; interleukin-6; tumor necrosis factor-alpha.

OBJECTIVE

Thalidomide has been shown to have antitumor activity in some patients with advanced hepatocellular carcinoma (HCC). We initiated a phase II study to determine the safety and efficacy of adding metronomic chemotherapy to thalidomide as first-line therapy.

METHODS

This open- labeled, single-arm, multicentered, investigator-initiated study enrolled patients with treatment-naïve advanced HCC not amenable to locoregional therapies. Treatment included oral thalidomide (100 mg twice daily) and tegafur/uracil [125 mg/m(2) (based on tegafur) twice daily]. Tumor assessment was performed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. Pretreatment plasma levels of angiogenesis factors were correlated with patient outcomes.

RESULTS

Forty-three patients were included. Sixteen (37%) patients had a Cancer of the Liver Italian Program (CLIP) score of 4, and <em>31</em> (72%) patients had chronic hepatitis B virus infection. The objective response rate was 9%, and the disease stabilization rate was 33%. The median progression-free survival was 1.9 months (95% CI 1.7-2.1 months), and the median OS was 4.6 months (95% CI 2.3-6.9 months). Treatment was generally tolerable. High baseline plasma levels of <em>interleukin</em> (IL)-6 and IL-8 were adversely correlated with patient survivals.

CONCLUSIONS

The combination of thalidomide and tegafur/uracil was safe and demonstrated modest activity in patients with advanced HCC.

Between January 2001 and September 2007, we treated 54 metastatic melanoma patients with patient-specific tumor cell vaccines consisting of dendritic cells (DCS), derived from their peripheral blood cells that were cultured in <em>interleukin</em> (IL)-4 and granulocyte macrophage colony-stimulating factor (GM-CSF), which had phagocytosed irradiated autologous tumor cells from a continuously proliferating, self-renewing, autologus tumor cell (TC) culture. The loaded DCs were injected subcutaneously in 500 microg of GM-CSF weekly x three, and then monthly for 5 months, for a total of up to 8 injections. The 34 men and 20 women had a median age of 50.5 years; 32 had M1c (visceral metastases and/or elevated lactate dehydrogenase) as their most advanced disease stage. Overall, 83% had received other systemic therapies, including interferon-alpha (n = 20), biochemotherapy (n = 19), GM-CSF (n = 19), chemotherapy (n = 16), IL-2 (n = 13), and other investigational vaccines (n = 7). Patients received an average of 7.4 vaccinations. Treatment was well-tolerated, with most patients experiencing only mild local pruritus and/or erythema. A positive delayed-type hypersensitivity reaction to purified autologous tumor cells was observed at baseline in only 1 of 54 patients, compared to 12 of 54 following vaccination (p = 0.001). The projected 5-year survival rate is an impressive 54% at a median follow-up of 4.5 years (range, 2.4-7.4) for the 30 surviving patients. This survival was superior to that observed following vaccination with irradiated TC in 48 melanoma patients in a previous trial (64 versus <em>31</em> months, p = 0.016). This patient-specific vaccine warrants further investigation, based on its safety and encouraging survival rates. (

BACKGROUND

NCI-V01-1646).

OBJECTIVE

Intra-amniotic infection/inflammation (IAI) is causally linked with spontaneous preterm labor and delivery. The ST2L receptor and its soluble form (sST2) are capable of binding to interleukin (IL)-33, a member of the IL-1 superfamily. Members of this cytokine family have been implicated in the onset of spontaneous preterm labor in the context of infection. Soluble ST2 has anti-inflammatory properties, and plasma concentrations are elevated in systemic inflammation, such as sepsis, acute pyelonephritis in pregnancy and the fetal inflammatory response syndrome. The aims of this study were to examine: (1) whether amniotic fluid concentrations of sST2 change with IAI, preterm, and term parturition; and (2) if mRNA expression of ST2 in the chorioamniotic membranes changes with acute histologic chorioamnionitis in women who deliver preterm.

METHODS

A cross-sectional study was conducted to determine amniotic fluid concentrations of sST2 in: (1) women with preterm labor (PTL) who delivered at term (n=49); (2) women with PTL who delivered preterm without IAI (n=21); (3) women with PTL who delivered preterm with IAI (n=31); (4) term pregnancies not in labor (n=13); and (5) term pregnancies in labor (n=43). The amniotic fluid concentration of sST2 was determined by ELISA. The mRNA expression of ST2 in the chorioamniotic membranes of women who delivered preterm with (n=24), and without acute histologic chorioamnionitis (n=19) was determined by qRT-PCR.

RESULTS

(1) Patients with PTL who delivered preterm with IAI had a lower median amniotic fluid concentration of sST2 compared to those with PTL who delivered preterm without IAI [median 410 ng/mL, inter-quartile range (IQR) 152-699 ng/mL versus median 825 ng/mL, IQR 493-1216 ng/mL; p=0.0003] and those with PTL who delivered at term [median 410 ng/mL, IQR 152-699 ng/mL versus median 673 ng/mL, IQR 468-1045 ng/mL; p=0.0003]; (2) no significant differences in the median amniotic fluid concentration of sST2 were observed between patients with PTL who delivered at term and those who delivered preterm without IAI (p=0.4), and between women at term in labor and those at term not in labor (p=0.9); (3) the mean mRNA expression of ST2 was 4-fold lower in women who delivered preterm with acute histologic chorioamnionitis than in those without this lesion (p=0.008).

CONCLUSIONS

The median sST2 amniotic fluid concentration and mRNA expression of ST2 by chorioamniotic membranes is lower in PTL associated with IAI and acute histologic chorioamnionitis than in PTL without these conditions. Changes in the median amniotic fluid sST2 concentration are not observed in preterm and term parturition without IAI. Thus, amniotic fluid sST2 in the presence of IAI behaves differently when compared to sST2 in the plasma of individuals affected by fetal inflammatory response syndrome, acute pyelonephritis in pregnancy, and adult sepsis. Decreased concentrations of sST2 in IAI are likely to promote a pro-inflammatory response, which is important for parturition in the context of infection.

Troglitazone has recently been introduced in the treatment of Type 2 diabetes. In addition to its anti-diabetic effects it acts as a perixosome proliferator activated receptor-gamma (PPAR-gamma) agonist and has anti-inflammatory properties by inhibiting macrophage tumour necrosis factor-alpha (TNF-alpha) secretion. It also inhibits the production of endothelial selectin (e-selectin). Troglitazone also reduces <em>interleukin</em>-1alpha induced nitric oxide production in pancreatic beta-cells, which may be relevant in preventing nitric oxide mediated damage to these cells in the Type 1 diabetes process. We tested troglitazone in the spontaneous model of autoimmune diabetes, the non-obese diabetic (NOD) mouse, to determine its effect on the disease process. When administered by gavage from weaning at a dose of 400 mg/kg body weight (n = 32), troglitazone reduced the incidence of diabetes by 16 weeks compared to controls (n = 32) in a pattern that was maintained up to the conclusion of the experiment at <em>31</em> weeks of age (p < 0.05). Insulitis was unaltered (index = 1.05 +/- 0.71 vs. 1.13 +/- 0.82, treated vs. controls, p = 0.78). The study was repeated using troglitazone in the diet of NOD mice (n = 24) to give a dose of approximately 200 mg/kg body weight in order to provide a more consistent level of troglitazone during the time course of the experiment. There was a reduction of diabetes incidence in this group but it did not reach significance. Insulin levels were reduced in gavage treated mice although such reduction did not reach significance (p < 0.07). We conclude that, in view of its effect on this model of autoimmune diabetes and because of its known function as an insulin sensitiser, troglitazone might be considered for potential use in those patients with Type 1 masquerading as Type 2 diabetes.

BACKGROUND

A subset of interleukin (IL)-10-producing regulatory B (Breg) cells that suppress T-cell-mediated immunity was recently identified; however, their role in chronic hepatitis B (CHB) remains elusive.

OBJECTIVE

To explore the possible role of Breg in the interaction with Th cells and consequent pathogenesis of CHB.

METHODS

The prevalence of Breg as well as 3 major effector T-cell subsets--CD4(+)CD25(high)Foxp3(+) regulatory T (Treg) cells, T helper 1 cells (Th1), and T helper 2 cells (Th2)--was assessed in the peripheral blood of 31 patients with CHB, 28 patients with acute hepatitis B (AHB), and 25 healthy controls (HC).

RESULTS

Compared to patients with AHB and HC, the prevalence of Breg and Treg cells and the concentration of IL-10 in the supernatant of cultured peripheral blood mononuclear cells (PBMCs) were greatly increased in patients with CHB. A significantly decreased proportion of Th1 cells was also observed in patients with CHB and was demonstrated to have a negative correlation with the prevalence of Breg. Furthermore, depletion of Treg cells in the PBMCs of patients with CHB did not alter the frequency of Breg cells or their ability to produce IL-10, indicating little, if any, impact of Treg cells on the generation and maintenance of Breg cells.

CONCLUSIONS

Our data indicate that increased Breg cells might be a major source of elevated IL-10 in CHB and represent a critical and independent regulatory force in the development of impaired anti-HBV immunity, consequently contributing to the pathogenesis of CHB.

The combination of high levels of beta2-microglobulin (beta2-m) and chromosome 13 deletion allows identification of a high-risk subgroup of patients with de novo multiple myeloma (MM). In this population of patients, we have evaluated the impact of a murine anti-<em>interleukin</em> 6 (anti-IL-6) monoclonal antibody (BE-8) as part of the second conditioning regimen in a multicenter prospective randomized trial of tandem autologous stem cell transplantation (ASCT). Conditioning for the first ASCT was accomplished with melphalan 200 mg/m2 and for the second one with melphalan 220 mg/m2 plus dexamethasone with or without BE-8 infusion. This trial included 219 patients, of whom 166 were randomized, 85 without BE-8 (arm A) and 81 with BE-8 (arm B). The median overall survival (OS) and event-free survival (EFS) times of the whole group of patients were 41 and 30 months, respectively. Response rates, OS, and EFS were not different between the 2 arms of the trial. OS at 54 months was 46% in arm A and 51% in arm B (P = .90); median EFS was 35 months in arm A and <em>31</em> in arm B (P = .39). In high-risk patients the dose intensity of melphalan at 420 mg/m2 led to encouraging results, but the addition of anti-IL-6 monoclonal antibody to the second conditioning regimen did not improve either OS nor EFS.