Serum and cerebrospinal fluid (CSF) from <em>31</em> patients with multiple sclerosis (MS) were examined to determine the levels of tumor necrosis factor (TNF) and <em>interleukin</em> (IL)-1 alpha (or IL-1 beta) by an enzyme-linked immunosorbent assay. TNF was detected in 29 (93.5%) of CSF from <em>31</em> cases of MS. TNF was also detectable in 100% of CSF from patients with acute relapsing MS in exacerbation. Patients with acute relapsing MS in exacerbation showed significantly higher CSF levels of TNF as compared with either those in remission or the controls (P less than 0.001 and P less than 0.0001, respectively). Increased levels of TNF were also detected in 35.5% of the MS sera, and especially in those with acute relapsing MS in exacerbation. Increased TNF levels were also frequent in the CSF and sera of patients with Guillain-Barré syndrome (GBS), which is also a demyelinating disease. No IL-1 alpha (or IL-1 beta) was detected in either CSF or sera of <em>31</em> MS patients. It is considered likely that TNF CSF levels may reflect disease activity in MS.

OBJECTIVE

Laparoscopic cholecystectomy is a so called mini-invasive surgical procedure, and on this basis, we investigated whether and how the immune response is modified in patients after laparoscopic cholecystectomy compared to patients who underwent open cholecystectomy.

METHODS

In a prospective, nonrandomized trial, 35 patients underwent laparoscopic cholecystectomy and <em>31</em> open cholecystectomy. Immune activity (neutrophils, total lymphocytes, lymphocyte subpopulations, human leukocyte antigen (HLA-DR), <em>interleukin</em> 6, skin Multitest) was evaluated before surgery and respectively, 1, 3, and 6 days postoperatively.

RESULTS

One day after surgery, an increase in interleukin 6 (P < 0.01) was noted in patients who had undergone open cholecystectomy, while this parameter was almost unchanged in patients with laparoscopic cholecystectomy. Moreover, skin tests showed a hypo or anergic response in the majority (81.8%) of open cholecystectomy patients compared to laparoscopic cholecystectomy patients (10.5%), (P < 0.01). Finally, monocyte antigen HLA-DR was also reduced in open cholecystectomy patients (P < 0.05). In this group, we noted 2 cases (6.45%) of respiratory tract infection.

CONCLUSIONS

Even though laparoscopic cholecystectomy requires a longer surgery, it reduces postoperative pain, and hospitalization. It also facilitates rapid recovery, a return to normal activity, avoids postoperative immunosuppression and shows a better postoperative morbidity compared to open surgery.

We have demonstrated, by using a T-cell transfer murine colitis model, that blocking <em>interleukin</em> 6 (IL-6) signaling with monoclonal antibody (mAb) to IL-6 receptor (IL-6R) abrogated apoptosis resistance of lamina propria T cells, suppressed the expression of vascular adhesion molecules, and successfully prevented and treated intestinal inflammation. Based on these results, we carried out an exploratory clinical trial to investigate the safety and efficacy of humanized anti-IL-6R mAb, MRA, in patients with Crohn's disease (CD). The results were promising, with 80% of the patients given every-2-week MRA infusions for 12 weeks showing a significantly higher clinical response rate as compared to <em>31</em>% of the placebo-treated patients. Twenty percent of the patients on this regimen went into remission as compared to 0% of the placebo group. The acute-phase responses were normalized by a single MRA infusion, which strongly suggests IL-6 is the major cytokine responsible for their production in CD.

OBJECTIVE

Increased interleukin-6 plasma levels have been reported in metabolic syndrome (MS); nevertheless, it is unclear whether interleukin-6 activity is exerted through direct signalling only or also through the "trans-signalling". This issue is important to clarify since signalling and "trans-signalling" affect different tissues. We investigated the relationship between MS and the interleukin-6 system in an older population.

METHODS

Data from 997 older community dwelling individuals (age ≥ 65 years; females: 56.2%) enrolled the InChianti study were analysed. Interleukin-6, soluble interleukin-6 receptor (sIL-6r), and soluble glycoprotein 130 (sgp130) were measured on plasma by ELISA. MS was defined by the NCEP ATP III criteria; 309 individuals (31%) resulted affected by MS.

RESULTS

Subjects with MS had higher interleukin-6 and sgp130 levels compared to controls; a trend toward higher levels of sIL-6R was also observed. The risk of having MS was increased in individuals with high sIL-6r or/and sgp130 levels, independent of age, gender, and interleukin-6 levels. Elevated sgp130 levels were associated with higher plasma glucose, HOMA, triglycerides, and with diabetes both in subjects with and without MS. Although the risk of high sgp130 levels was generally associated with MS (O.R.: 1.77, 95%C.I.: 1.39-2.25), this excess of risk was not present in MS phenotypes excluding the criteria "elevated glucose" or "elevated triglycerides". Furthermore, the association between sgp130 and MS disappeared after adjustment for HOMA.

CONCLUSIONS

We found that older individuals with MS have increased sgp130 plasma levels compared with controls; nevertheless, our data suggest that this association might be mediated by insulin resistance.

OBJECTIVE

Our purpose was to compare and correlate amniotic fluid GRO-alpha, interleukin-8, and L-selectin in patients with and without intraamniotic infection.

METHODS

Amniocentesis was performed on 45 pregnant women with preterm contractions, labor, or rupture of membranes. Fourteen patients had intraamniotic infection, and 31 did not. Intraamniotic infection was defined as the presence of a positive amniotic fluid culture. Amniotic fluid tests for Gram stain, glucose, neutrophil counts, creatinine, pH, and specific gravity were performed. Amniotic fluid levels of soluble L-selectin, interleukin-8, and GRO-alpha were measured by an enzyme-linked immunoassay and normalized by amniotic fluid creatinine levels. The Mann-Whitney Utest and Spearman's rank correlation test were used for statistical analyses.

RESULTS

Amniotic fluid median levels of soluble L-selectin, interleukin-8, and GRO-alpha were significantly higher in pregnant women with intraamniotic infection than in those without intraamniotic infection (soluble L-selectin: median 3334.6 ng/mg creatinine, range 408.4 to 15,956.8 vs 717.2 ng/mg creatinine, range 129.4 to 4601.9, p = 0.009; GRO-alpha: median 841.6 ng/mg creatinine, range 28.1 to 8591.7 vs 56.8 ng/mg creatinine, range 0.0 to 440.2, p < 0.0001; interleukin-8: median 4932.7 ng/mg creatinine, range 0.0 to 55,058.7 vs 28.3 ng/mg creatinine, range 0.0 to 1161.6, p = 0.0004). Patients with intraamniotic infection had significantly higher amniotic fluid leukocyte counts and leukocyte esterase activities and significantly lower amniotic fluid glucose concentrations compared with those without intraamniotic infection. Amniotic fluid GRO-alpha, interleukin-8, and soluble L-selectin were positively correlated, and each was positively correlated with amniotic fluid leukocytes and negatively correlated with amniotic fluid levels of glucose.

CONCLUSIONS

Our data indicate amniotic fluid GRO-alpha and interleukin-8 may be two potent leukocyte chemoattractants and activators, and L-selectin is rapidly shed from leukocytes in the amniotic fluid in patients with intraamniotic infection.

OBJECTIVE

Anti-cytokine therapy is reportedly useful in amyloid A (AA) amyloidosis complicating rheumatic diseases. However, to date no studies have directly compared the utility of tumour necrosis factor (TNF) inhibition to that of interleukin-6. The aim of our retrospective study was to compare the clinical utility of tocilizumab (TCZ) and anti-TNF (TNF inhibitor) therapy.

METHODS

We studied 42 patients treated with anti-cytokine agents at our hospital: 31 had received a single agent, ten had received two agents and one had received three agents. Patients were divided into a TCZ group (22 patients) and a TNF inhibitor group (32 patients). The main parameters compared were treatment retention rate, serum amyloid A (SAA) profile, renal function profile and clinical disease activity index.

RESULTS

The 5-year retention rates were 90.4 (TCZ group) and 34.3 % (TNF inhibitor group) (p = 0.0154, log-rank test). The median SAA fell from 219.2 μg/mL at treatment initiation to 5.0 μg/mL at last observation (TCZ), and from 143.6 to 38.1 μg/mL (TNF inhibitor) (p = 0.0194). Estimated glomerular filtration rate was improved in 72.7 (TCZ) and 34.4 % (TNF inhibitor) of patients (p = 0.0062). The rates of clinical remission or low disease activity at last observation for the TCZ and TNF inhibitor groups were 72.7 and 40.7 % (p = 0.0201), respectively.

CONCLUSIONS

Based on these results, we conclude that TCZ was of greater clinical utility than anti-TNF therapy in our patients with AA amyloidosis complicating rheumatic diseases.

We investigated the role of the complementarity determining region 1 (CDR1) of T cell receptor (TCR) beta chain both in antigen/major histocompatibility complex I (MHC I) and in superantigen (SAg)/MHC II complex recognition. Residues 26 to <em>31</em> of the V beta 10 domain of a TCR derived from an H-2Kd-restricted cytotoxic clone were individually changed to alanine, using site-directed mutagenesis, and the mutated TCR beta chains were transfected along with the wild-type TCR alpha chain into a TCR alpha-beta-T hydridoma. These mutations affected antigen/H-2Kd complex recognition, although to a different extent, as estimated by <em>interleukin</em> 2 production. Certain mutations also affected differently the recognition of two Staphylococcal toxins, exfoliative toxin and Staphylococcal enterotoxin C2, presented by HLA-DR1. Whereas mutation of residues D30 or T<em>31</em> affect the recognition of both toxins, residues T26, L27, and H29 are critical for the recognition of only one of the SAgs. These observations demonstrate the participation of the CDR1 region in the recognition of peptide/MHC class I as well as SAg/MHC II complexes.

Maturing Sprague-Dawley (S-D) rats develop obesity and skeletal muscle insulin resistance. To investigate the relationship between fat mass and insulin responses, we performed surgical removal of the epididymal and retroperitoneal depots of visceral adipose tissue (VF) or sham surgery (SHAM) in male rats aged 4 months. At sacrifice, 30 days later, the mass of visceral fat was 48% lower (p<0.05) in VF- compared to SHAM, while subcutaneous fat was essentially unchanged. VF- animals displayed increased insulin responses in isolated strips of skeletal muscle. Insulin-stimulated glucose transport was increased 28% in soleus muscle (p<0.05), with a trend toward a <em>31</em>% increase in extensor digitorum longus muscle (p=0.058). Glucose tolerance was not significantly affected by surgical fat removal. In VF- animals, serum resistin was reduced 26% (p<0.05) and serum adiponectin was reduced 30% (p<0.05), with trends for reductions in IL-4 (58% reduction, p=0.084) and IL-6 (56% reduction, p=0.123). TNF-alpha, leptin and free fatty acids (NEFAs) were unchanged. We conclude that in maturing S-D rats, increased visceral adiposity leads to an increase in systemic release in resistin and possibly <em>interleukins</em>. Elevation of circulating cytokines may play a role in the development of muscle insulin resistance.

OBJECTIVE

The relationship between systemic sclerosis (SSc) and interleukin 23 (IL-23), a cytokine associated with the differentiation of T lymphocytes, is unknown. We investigated serum IL-23 levels and their clinical association in patients with SSc.

METHODS

Serum IL-23 levels were examined by ELISA in 63 patients with SSc, 15 patients with systemic lupus erythematosus (SLE), and 31 healthy individuals. SSc patients comprised 25 with limited cutaneous SSc and 38 with diffuse cutaneous SSc.

RESULTS

Serum IL-23 levels were significantly elevated in SSc patients compared to patients with SLE (p < 0.05) and controls (p < 0.005). Elevated serum IL-23 levels were associated with the disease duration (p < 0.05) and the prevalence of pulmonary fibrosis (p < 0.05), although they were not associated with other clinical features, including the extent of skin sclerosis or the severity of pulmonary fibrosis.

CONCLUSIONS

The results suggest that IL-23 is associated with induction of SSc and that blockade of IL-23 can be a potential therapeutic strategy in early SSc.

BACKGROUND

Adiponectin has insulin-sensitizing and anti-atherosclerotic effects, partly mediated through its action on monocytes. We aimed to determine adiponectin levels and expression of its receptors (AdipoR1 and AdipoR2) in peripheral monocytes from overweight and obese patients with coronary artery disease (CAD).

METHODS

Fifty-five overweight/obese patients, suspected for CAD, underwent coronary angiography: <em>31</em> were classified as CAD patients (stenosis ≥ 50% in at least one main vessel) and 24 as nonCAD. Quantitative RT-PCR and flow cytometry were used for determining mRNA and protein surface expression of adiponectin receptors in peripheral monocytes. A high sensitivity multiplex assay (xMAP technology) was used for the determination of plasma adiponectin and <em>interleukin</em>-10 (IL-10) secreted levels.

RESULTS

Plasma adiponectin levels were decreased in CAD compared to nonCAD patients (10.9 ± 3.1 vs. 13.8 ± 5.8 μg/ml respectively, p = 0.033). In multivariable analysis, Matsuda index was the sole independent determinant of adiponectin levels. AdipoR1 and AdipoR2 protein levels were decreased in monocytes from CAD compared to nonCAD patients (59.5 ± 24.9 vs. 80 ± 46 and 70.7 ± 39 vs. 95.6 ± 47.8 Mean Fluorescence Intensity Arbitrary Units respectively, p < 0.05). No significant differences were observed concerning the mRNA levels of the adiponectin receptors between CAD and nonCAD patients. AdipoR2 protein levels were positively correlated with plasma adiponectin and Matsuda index (r = 0.36 and 0.<em>31</em> respectively, p < 0.05 for both). Furthermore, basal as well as adiponectin-induced IL-10 release was reduced in monocyte-derived macrophages from CAD compared to nonCAD subjects.

CONCLUSIONS

Overweight patients with CAD compared to those without CAD, had decreased plasma adiponectin levels, as well as decreased surface expression of adiponectin receptors in peripheral monocytes. This fact together with the reduced adiponectin-induced IL-10 secretion from CAD macrophages could explain to a certain extent, an impaired atheroprotective action of adiponectin.

OBJECTIVE

Interleukin (IL)-1 gene polymorphism has been reported to be associated with the increment of gastric cancer (GC) and the decrement of duodenal ulcers (DU). In addition, IL-2 is known to induce Helicobacter pylori (H. pylori)-associated gastric atrophy, but it is not known whether IL-2 gene polymorphism increases the risk of GC (GC) or peptic ulcer diseases. Therefore, we compared the genotypes of IL-1B, IL-1RN, and IL-2 gene polymorphisms with risk of gastric ulcers (GU), GC, and DU in Korean patients.

METHODS

In total, 116 GU, 122 GC, and 104 DU patients were included consecutively and compared with 100 healthy controls. Polymorphisms of the IL-1B-511/-31 gene, the penta-allelic variable number of tandem repeats of the IL-1RN gene, and the IL-2-330 gene were analyzed by polymerase chain reaction with restriction fragment length polymorphism or confronting two-pair primers methods.

RESULTS

The age-sex-adjusted odds ratios (OR) for the IL-1B-511 T genotype relative to the C/C genotype (OR = 0.82, 95% confidence interval [CI] 0.41-1.65), IL-1RN*2 genotype relative to the L/L genotype (OR = 0.85, 95% CI 0.41-1.78), and IL-2-330 T genotype relative to the G/G genotype (OR = 1.94, 95% CI 0.76-4.96) were not increased in GC. There was also no significant difference in the genotypes of these cytokine polymorphisms between the study group (GU or DU) and control group. In addition, genotypic frequency was not associated with H. pylori positivity and histological type of GC.

CONCLUSIONS

IL-1B-511, IL-1RN, and IL-2 genetic polymorphisms were not important contributors to the pathogenesis of GU, GC, and DU in Korean patients.

Alterations in cellular immune function are associated with depression and have been related to changes in endocrine function. We carried out a study to: (i) reliably assess the hypothalamic-pituitary-adrenal (HPA) axis function in treatment resistant depression (TRP); (ii) evaluate whether depression was associated with changes on T-cell proliferation and cytokine production; and (iii) assessed the sensitivity of lymphocytes to glucocorticoids (GC)s in vitro. Thirty-six pharmacologically treated inpatients diagnosed with TRP and <em>31</em> healthy controls took part in the study. Salivary cortisol was measured hourly from 0800 to 2200 h both before and after dexamethasone (DEX) intake and the patients were classified into HPA axis suppressors and nonsuppressors. The following were measured in vitro: (a) phytohemagglutinin-induced T-cell proliferation; (b) cytokine production (<em>interleukin</em>-2 and tumor necrosis factor-alpha, TNF-alpha); and (c) lymphocyte sensitivity to both cortisol and DEX. Basal morning cortisol levels from patients and controls did not differ nor did their T-cell proliferation and cytokine production. Ten out of 36 patients were classified as nonsuppressors and presented a significantly higher post-DEX salivary cortisol levels than suppressors, 82.0 vs 8.9 nM/l/h (p <0.001). Cells of nonsuppressors produced significantly less TNF-alpha compared to suppressors, 299.8 vs 516.9 pg/ml (p < 0.05). Remarkably, GC-induced suppression of lymphocyte proliferation and cytokine production were generally less marked in depressives compared with controls. Our data indicate that alterations in immune function and steroid regulation associated with depression are not related to elevated basal levels of cortisol and suggest that lymphocyte steroid resistance may be associated with TRP.

Definitions of the metabolic syndrome (MetS) include obesity, dyslipidemia, elevated levels of fasting blood glucose, and blood pressure as criteria, but it is also known that the MetS is associated with chronic, subclinical inflammation. Hyperglycemia (fasting and postprandial) may be important in exacerbating this proinflammatory state. We aimed to assess the impact of oral glucose challenge and in vitro glucose-stimulation on gene expression and secretion of inflammatory parameters in peripheral blood leukocytes and to investigate whether presence of the MetS could "prime" leukocytes to up-regulate proinflammatory markers in response to glucose. Using quantitative real-time PCR, we could show that the expression of intercellular adhesion molecule 1 (ICAM-1), tumor necrosis factor alpha (TNF-alpha), and <em>interleukin</em> 6 (IL-6) significantly increased in peripheral blood leukocytes from "MetS" subjects (n=39) compared to "no MetS" subjects (n=35) 2 h after an oral glucose tolerance test (ICAM-1 +52%, TNF-alpha +107%, and IL-6 +38%) and also in vitro after 72 h cultivation in high-glucose medium (ICAM-1 +74%, TNF-alpha +71%, and IL-6 +44%). Using ELISA and Luminex technique, we further observed a trend towards increased immune mediator concentrations in the corresponding cell culture supernatants from MetS patients (ICAM-1 +21%, TNF-alpha +<em>31</em>%, and IL-6 +175%). Thus, the MetS may support peripheral inflammation by sensitizing leukocytes to up-regulate proinflammatory markers in response to glucose, which in turn increases the risk for type-2 diabetes mellitus and cardiovascular disease.

BACKGROUND

Appendixes removed from patients with suspected appendicitis often appear normal on histological examination. We examined appendix specimens for expression of abnormal amounts of cytokines, an indicator of an inflammatory response.

METHODS

Tumour necrosis factor alpha (TNFalpha) and <em>interleukin</em>-2 (IL-2) expression was measured by in-situ hybridisation in ten specimens from patients with acute appendicitis, 12 normal appendix specimens removed from patients undergoing elective abdominal surgery, and <em>31</em> appendix specimens from patients with a clinical diagnosis of appendicitis but an appendix histologically classified as normal. Cytokine-specific RNA antisense probes were prepared by in-vitro transcription and digoxigenin (DIG) labelled. In-situ hybridisation was done on 5 micrometer paraffin sections. Tissue sections hybridised by sense probes acted as negative control for each cytokine. Following hybridisation, the probes were detected by alkaline phosphatase labelled anti-DIG monoclonal antibody and visualised by nitroblue tetrazolium staining.

RESULTS

All histologically proven acute appendicitis specimens demonstrated intense cellular TNFalpha mRNA expression in germinal centres and moderate levels of expression throughout the mucosa. IL-2 mRNA was strongly expressed in the lamina propria and only moderately expressed in germinal centres. Normal appendixes all showed almost complete absence of TNFalpha and IL-2 mRNA expression. Seven of the <em>31</em> histologically classified normal appendix specimens from patients with a clinical diagnosis of appendicitis demonstrated TNFalpha and IL-2 mRNA expression similar to acute appendicitis specimens in germinal centres, submucosa, and lamina propria layers.

CONCLUSIONS

TNFalpha and IL-2 mRNA expression is a sensitive marker of inflammation in appendicitis. A substantial proportion of histologically normal appendixes showed clear evidence of an inflammatory response in the form of increased cytokine expression.

Concerns have been raised regarding an increased risk of major adverse cardiovascular events (MACEs) (myocardial infarction, cerebrovascular accident or cardiovascular death) in patients treated with anti-<em>interleukin</em> (IL)-12/23 agents for moderate-to-severe psoriasis. We aimed to examine the risk of MACEs in adult patients with plaque psoriasis that are exposed to biologic therapies via a meta-analysis of randomized controlled trials (RCTs). Data were obtained from systematic searches in the Cochrane Library, MEDLINE and Embase, U.S. Food and Drug Administration, European Medicines Agency, individual pharmaceutical companies online search platforms and five trials registers (up to <em>31</em> March 2016). We selected RCTs reporting adverse events in adults with plaque psoriasis receiving at least one licensed dose of biologic therapy, conventional systematic therapy or placebo. We calculated Peto odds ratios (ORs) with 95% confidence intervals (CIs) and calculated I2 statistics to assess heterogeneity. Overall, 38 RCTs involving 18 024 patients were included. No MACEs were observed in 29 studies, while nine RCTs reported 10 patients experiencing MACEs. There was no statistically significant difference in risk of MACEs associated with the use of biologic therapies overall (OR 1·45, 95% CI 0·34-6·24); tumour necrosis factor-α inhibitors (adalimumab, etanercept and infliximab) (OR 0·67, 95% CI 0·10-4·63); anti-IL-17A agents (secukinumab and ixekizumab) (OR 1·00, 95% CI 0·09-11·09) or ustekinumab (OR 4·48, 95% CI 0·24-84·77). No heterogeneity was observed in these comparisons. In conclusion, the limited existing evidence suggests that licensed biologic therapies are not associated with MACEs during the short randomized controlled periods in clinical trials.

We investigated treatment with gemtuzumab ozogamicin (GO) in 51 patients aged 65 years or older with newly diagnosed acute myeloid leukemia (AML), refectory anemia (RA) with excess of blasts in transformation, or RA with excess blasts. GO was given in doses of 9 mg/m(2) of body-surface area on days 1 and 8 or, therapeutically equivalently, on days 1 and 15, with or without <em>interleukin</em> 11 (IL-11; 15 microg/kg per day on days 3 to 28), with assignment to IL-11 treatment made randomly. Complete remission (CR) rates were 2 of 26 (8%) for GO without IL-11 and 9 of 25 (36%) for GO with IL-11. Regression analyses indicated that IL-11 was independently predictive of CR but not survival. We compared GO with or without IL-11 with idarubicin plus cytosine arabinoside (IA), as previously administered, in similar patients. The CR rate with IA was 15 of <em>31</em> (48%), and survival was superior with IA compared with GO with or without IL-11 (P =.03). Besides accounting for possible covariate effects on outcome, we also accounted for possible trial effects (TEs) arising because IA and GO with or without IL-11 were not arms of a randomized trial. Bayesian posterior probabilities that GO with or without IL-11 produced longer survival than IA, after accounting for covariates and TEs, were less than 0.01 in patients with abnormal cytogenetic findings (AC) and less than 0.15 in patients with normal cytogenetic findings (NC). Regarding CR, the analogous probabilities were less than 0.02 for GO without IL-11 (all cytogenetic groups), and for GO with IL-11, less than 0.25 for AC groups and about 0.50 for NC groups. TEs 2 to 5 times the magnitude of those previously observed would be needed to conclude that survival with GO with or without IL-11 is likely longer than with IA. Thus, there is little evidence to suggest that GO with or without IL-11 should be used instead of IA in older patients with newly diagnosed AML or myelodysplastic syndrome.

Although reduced natural killer (NK) cell levels have been reported consistently in patients with coronary artery disease (CAD), the clinical significance and persistence of this immune perturbation is not clarified. In this study we characterized the NK cell deficit further by determining (i) differentiation surface markers and cytokine profile of NK cell subsets and (ii) ability to reconstitute NK cell levels over time. Flow cytometry was used to analyse NK cell subsets and the intracellular cytokine profile in <em>31</em> patients with non-ST elevation myocardial infarction (non-STEMI), 34 patients with stable angina (SA) and 37 healthy controls. In blood collected prior to coronary angiography, the proportions of NK cells were reduced significantly in non-STEMI and SA patients compared with controls, whereas NK cell subset analyses or cytokine profile measurements did not reveal any differences across groups. During a 12-month follow-up, the proportions of NK cells increased, although not in all patients. Failure to reconstitute NK cell levels was associated with several components of metabolic syndrome. Moreover, <em>interleukin</em> (IL)-6 levels remained high in patients with sustained NK cell deficit, whereas a decline in IL-6 (P < 0·001) was seen in patients with a pronounced increase in NK cells. In conclusion, we found no evidence that reduction of NK cells in CAD patients was associated with aberrations in NK cell phenotype at any clinical stage of the disease. Conversely, failure to reconstitute NK cell levels was associated with a persistent low-grade inflammation, suggesting a protective role of NK cells in CAD.

OBJECTIVE

The slow asymptomatic progression of chronic hepatitis C (CHC) can be interrupted by an acute exacerbation, characterized by increased serum levels of alanine aminotransferase (ALT) and bilirubin and other symptoms of acute hepatitis. We aimed to provide more information about the clinical presentation of acute exacerbation of CHC.

METHODS

We identified 82 consecutive patients, from 2 locations in Italy, who had an acute exacerbation of CHC from January 2005 through June 2010; we followed them up for a median period of 36 months. These cases were hepatitis C virus (HCV) RNA positive, hepatitis B surface antigen-negative, and had not received anti-HCV therapy. They were matched with 82 subjects with hepatitis C without reactivation for age, sex, and HCV genotype (controls). Sixty-nine cases and 73 controls were followed up for at least 2 years. Liver biopsy specimens had been taken from 23 cases and <em>31</em> controls-once before enrollment in the study and once during the follow-up period.

RESULTS

HCV genotype 2 was detected in 46.4% of cases, and HCV genotype 1 was detected in 43.9%. Among cases, the mean ALT level was 1063 ± 1038 IU/dL, and the mean total bilirubin level was 15.87 ± 7.15 mg/dL. A higher percentage of cases carried the interleukin-28B CC genotype than controls (40.2% vs 24.4%; P < .05). Among cases, 43.5% had a steady increase in ALT level (>2-fold baseline value); for 56.5% of these patients, ALT levels returned to baseline values before the acute exacerbation of chronic hepatitis. Based on comparisons of biopsy specimens, 18 cases (78.3%) and 11 controls (35.5%) had increasing fibrosis, with Ishak scores increasing by more than 2 (P < .005); 14 cases (60.9%) and 3 controls (9.6%) had increases in necroinflammation of more than 2 points (P < .005). Thirty-two cases (46.4%) and 38 controls (52%) received treatment with pegylated interferon and ribavirin; a sustained virologic response was achieved in 26 cases (81.2%) and 23 controls (60.5%).

CONCLUSIONS

Although an acute exacerbation of chronic hepatitis is a serious medical condition, most patients achieve a sustained virologic response after treatment with pegylated interferon and ribavirin.

<AbstractText>Breast cancer is currently the most common neoplasm diagnosed in women globally. There is a growing body of evidence to suggest that human papillomavirus (HPV) infection may play a key role in invasiveness of breast cancer. The aim of this study was to determine the presence of HPV in patients with breast cancer and its possible association with cancer progression.</AbstractText><AbstractText>Breast specimens were collected from 72 patients with breast cancer and <em>31</em> healthy controls. The presence of HPV was investigated by polymerase chain reaction (PCR) and genotyping was performed for positive cases. We also evaluated the viral factors such as E6, E2, and E7 in HPV positive cases. Enzyme-linked immunosorbent assay (ELISA (and Real-time PCR techniques were used to measure the expression level of anti-carcinogenic genes, such as p53, retinoblastoma (RB), breast and ovarian cancer susceptibility gene (BRCA1, BRCA2) and inflammatory cytokines, including tumor necrosis factor α (TNF-α), transforming growth factor β (TGF-β), nuclear factor-kB (NF-kB), and different <em>interleukins</em> [ILs] (IL-1,IL6, and IL-17).</AbstractText><AbstractText>The HPV DNA was detected in 48.6% of breast cancer samples, whereas only 16.1% of controls were positive for HPV. We observed statistically significant differences between breast cancer patients and HPV presence (P = 0.003). HPV type 18 was the most prevalent virus genotype in patients. The expression of P53, RB, BRCA1, and BRCA2 were decreased in patients with HPV-positive breast cancer as compared to HPV-negative breast cancer and healthy controls. (All P-values were less than 0.05). The presence of the HPV was associated with increased inflammatory cytokines (IL-1, IL-6, IL-17, TGF-β, TNF-α, and NF-kB) and tumor progression.</AbstractText><AbstractText>The present study demonstrated that HPV infection may implicate in the development of some types of breast cancer.</AbstractText>

BACKGROUND

Cognitive impairment strikingly reduces the quality of life of Parkinson's disease (PD) patients. Studies find that pathological proteins, neuroinflammatory factors and free radicals may involve in the pathogenesis of cognitive impairment of PD, however, results are inconclusive.

METHODS

We recruited 62 PD patients and <em>31</em> healthy controls. PD patients were identified with cognitive impairment, including PD with mild cognitive impairment (PD-MCI) and PD with dementia (PDD) according to the diagnostic criteria for PD-MCI and PDD issued by Movement Disorder Society Task Force. The levels of pathological proteins, including β-amyloid 1-42 (Aβ1-42),Total-tau (T-tau) and phosphorelated tau (P-tau), neuroinflammatory factors,including tumor necrosis factor-α (TNF-α), <em>interleukin</em>-1β (IL-1β), <em>interleukin</em>-6 (IL-6), interferon-γ (INF-γ) and prostaglandin E2 (PGE2), free radicals, including hydroxyl radical (·OH), hydrogen peroxide (H2O2) and nitric oxide (NO) in cerebrospinal fluid(CSF) were detected. The levels of above factors in CSF were compared among healthy controls and patients with and without cognitive impairment. Correlation analyses were performed between Montreal Cognitive Assessment (MoCA) score and the levels of above factors in CSF.

RESULTS

T-tau level in CSF from PD-CI patients are significantly elevated comparing with those without cognitive impairment and controls (P = 0.016 and 0.004, respectively). The levels of P-tau (S396) and · OH in PD-CI patients are significantly higher than controls (P = 0.001 and 0.014, respectively). IL-6 levels in PD-CI patients are strikingly enhanced comparing with those without cognitive impairment (P = 0.005). MoCA score is negatively correlated with the levels of T-tau (r = -0.340), P-tau (S396) (r = -0.448), IL-6 (r = -0.489) and · OH (r = -0.504) in PD-CI patients.

CONCLUSIONS

Elevated levels of T-tau, P-tau (S396), IL-6 and · OH in CSF are significantly correlated with cognitive impairment in PD patients. This investigation may suggest the potential biomarkers relating pathological proteins, neuroinflammatory factors and free radicals in PD patients with cognitive impairment.

BACKGROUND

<em>Interleukin</em>-<em>31</em> (IL-<em>31</em>) is a member of the gp130/<em>interleukin</em>-6 cytokine family that is produced by cell types such as T helper 2 lymphocytes and cutaneous lymphocyte antigen positive skin homing T cells. When overexpressed in transgenic mice, IL-<em>31</em> induces severe pruritus, alopecia and skin lesions. In humans, IL-<em>31</em> serum levels correlate with the severity of atopic dermatitis in adults and children.

OBJECTIVE

To determine the role of IL-<em>31</em> in canine pruritus and naturally occurring canine atopic dermatitis (AD).

METHODS

Purpose-bred beagle dogs were used for laboratory studies. Serum samples were obtained from laboratory animals, nondiseased client-owned dogs and client-owned dogs diagnosed with naturally occurring AD.

METHODS

Purpose-bred beagle dogs were administered canine <em>interleukin</em>-<em>31</em> (cIL-<em>31</em>) via several routes (intravenous, subcutaneous or intradermal), and pruritic behaviour was observed/quantified via video monitoring. Quantitative immunoassay techniques were employed to measure serum levels of cIL-<em>31</em> in dogs.

RESULTS

Injection of cIL-<em>31</em> into laboratory beagle dogs caused transient episodes of pruritic behaviour regardless of the route of administration. When evaluated over a 2 h period, dogs receiving cIL-<em>31</em> exhibited a significant increase in pruritic behaviour compared with dogs that received placebo. In addition, cIL-<em>31</em> levels were detectable in 57% of dogs with naturally occurring AD (≥ 13 pg/mL) but were below limits of quantification (<13 pg/mL) in normal, nondiseased laboratory or client-owned animals.

CONCLUSIONS

Canine IL-<em>31</em> induced pruritic behaviours in dogs. Canine IL-<em>31</em> was detected in the majority of dogs with naturally occurring AD, suggesting that this cytokine may play an important role in pruritic allergic skin conditions, such as atopic dermatitis, in this species.

To determine the clinical utility of serum levels of chemokines and cytokines for the evaluation of disease activity in patients with systemic sclerosis (SSc), concentrations of four chemokines (interferon γ-inducible protein-10 [IP-10, CXCL10], monokine induced by interferon γ [MIG/CXCL9], monocyte chemoattractant protein-1 [MCP-1/CCL2], <em>interleukin</em> 8 [IL-8/CXCL8]) and six cytokines (IL-2, IL-4, IL-6, IL-10, tumor necrosis factor [TNF]-α, interferon [IFN]- γ) were measured using cytometric beads array kits in serum samples from <em>31</em> Japanese patients with SSc and 20 normal controls. Clinical and laboratory data and serum chemokine and cytokine levels were assessed for each patient at their first visit and each subsequent year for 3 years. Among these chemokines and cytokines, serum levels of IP-10, MIG and MCP-1 were significantly elevated in SSc patients compared with normal controls at their first visit. Serum MCP-1 levels declined year and year, along with improvement for skin sclerosis. The variations of MCP-1, but not IP-10 and MIG, were significantly associated with the variations of skin thickness score and vital capacity during 3 years. These results suggest that MCP-1 is a serological indicator of the activity of skin and lung involvement in patients with SSc. However, a longer-term prospective study in a larger population will be needed to confirm its clinical utility as predictors of outcomes.

BACKGROUND

Obstructive sleep apnea (OSA) is closely related to systemic inflammation. Resistin is an adipocyte-derived cytokine (adipokine) that may link obesity with inflammation.

OBJECTIVE

We aimed to investigate whether incremental changes in OSA severity, from normal to severe, primarily affect the levels of resistin and other adipokines.

METHODS

Serum levels of resistin, <em>interleukin</em>-6 (IL-6) and leptin were examined in <em>31</em> men with OSA and 10 men without OSA, matched for age, body mass index (BMI) and several metabolic profiles. In 11 of the <em>31</em> men with OSA, these mediators were reexamined after 3 months of nasal continuous airway pressure (nCPAP) therapy.

RESULTS

Levels of resistin and IL-6 were simultaneously elevated in men with OSA compared with those in men without OSA (p < 0.05), while levels of leptin did not differ. The resistin and IL-6 levels tended to increase with increasing disease severity (p < 0.05), which was based on the apnea-hypopnea index (AHI). The average oxyhemoglobin saturation during sleep (p < 0.01) and IL-6 (p < 0.05) emerged as significant determinants of resistin, even after adjustments for age, BMI, leptin levels and metabolic risk factors. After nCPAP therapy, the elevated levels of resistin and IL-6 decreased, reaching almost baseline levels of controls. Before treatment, AHI correlated positively with the reduction rate in resistin (p < 0.05).

CONCLUSIONS

In OSA patients, resistin production can be enhanced by hypoxic stress during sleep, possibly mediating systemic inflammatory processes. nCPAP therapy may play a beneficial role in the control of resistin production.

OBJECTIVE

Obesity, systemic inflammation and changes in the heart functions are associated with increased cardiovascular risk. This study aimed to investigate coronary microvascular dysfunction as an early marker of atherosclerosis in obese patients without any evidence of cardiovascular disease.

RESULTS

86 obese subjects (aged 44 ± 12 years, body mass index (BMI) 41 ± 8 kg m(-2)), without evidence of heart disease, and 48 lean controls were studied using transthoracic Doppler echocardiography for detecting coronary flow reserve (CFR). A value of CFR ≤ 2.5 was considered abnormal. We measured <em>interleukin</em>-6 (IL-6), tumour necrosis factor-α (TNF-α) and adiponectin in all patients. Patients with abnormal CFR underwent coronary multislice computed tomography (MSCT) in order to exclude an epicardial stenosis. CFR in obese subjects was lower than in lean subjects (3.2 ± 0.8 vs. 3.7 ± 0.7, p = 0.02) and was abnormal in 27 (<em>31</em>%) obese patients and in one (2%) control (p < 0.0001). All subjects with abnormal CFR showed no coronary stenosis at MSCT. At multivariable analysis, IL-6 and TNF-α were the only determinants of CFR (p < 0.02 and p < 0.02, respectively). At multivariable logistic regression analysis, IL-6 and TNF-α were the only determinants of CFR ≤ 2.5 (p < 0.03 and p < 0.03, respectively).

CONCLUSIONS

CFR is often reduced in obese subjects without clinical evidence of heart disease, suggesting a coronary microvascular impairment. This microvascular dysfunction seems to be related to a chronic inflammation mediated by adipocytokines. Our findings may explain the increased cardiovascular risk in obesity, independently of BMI.