Recent advances in pruritus research have elucidated mediators and neuronal pathways involved in itch transmission, and this fast emerging knowledge may possibly be translated into new therapies in the near future. In the skin and peripheral nerves, potential mediator and receptor therapeutic targets include the H4 histamine receptor, protease-activated receptor 2, serine proteases, cathepsin S, peripheral mu- and kappa-opioid receptors, <em>interleukin</em>-<em>31</em>, transient receptor potential vanilloid 1 and 3, fatty acid amide hydrolase, nerve growth factor and its receptor, acetylcholine, and the Mas-related G protein-coupled receptors. In the spinal cord, gastrin-related peptide and its receptor, as well as substance P and its receptor neurokinin receptor-1 serve as potential therapeutic targets. In the brain, reduction of itch perception and modulation of emotions may possibly be achieved through drugs acting on the anterior cingulate cortex. Clinically, management of pruritus should be instituted early and should address the skin pathology, peripheral neuropathy, central sensitization, and the cognito-affective aspects of the disease.

BACKGROUND

The contribution of local and systemic inflammation to the pathophysiology of sporadic first trimester miscarriages remains unclear. The objective of this study was to investigate the inflammatory response in the circulation of women presenting with first trimester miscarriage.

METHODS

Levels of tumour necrosis factor alpha (TNFα), TNF receptors 1 and 2, interferon gamma (IFNγ), <em>interleukin</em> (IL)-6 and IL-10 were assayed using cytometric bead arrays in plasma samples from 29 euploid and 21 aneuploid missed miscarriages, 35 normal pregnant controls and <em>31</em> non-pregnant women (NPW). Whole blood flow cytometry was carried out with samples from 17 euploid and 16 aneuploid miscarriages, 18 pregnant controls and 13 NPW.

RESULTS

The plasma of women with euploid miscarriage contained significantly higher circulating levels of TNFα (P < 0.005), IFNγ (P < 0.005), IL-6 (P < 0.005) and IL-10 (P < 0.01) than that of pregnant controls, irrespective of gestational age. Significantly (P < 0.05) higher TNF-R1 levels at 6-9 weeks, and significantly higher TNFα/IL-6 (P < 0.001) and significantly lower TNFα/IL-10 (P < 0.001) and IFNγ/IL-10 (P < 0.001) ratios at 10-14 weeks, were also found in euploid miscarriage cases compared with pregnant controls. TNFα/IL-10 ratio in plasma was significantly (P < 0.05) lower in miscarriages with an abnormal karyotype than those with normal karyotype. Normal pregnant women had a significantly higher plasma level of IFNγ (P < 0.01) and IFNγ/IL-10 ratio (P < 0.005), a significantly (P < 0.005) lower TNF-R1 level, and a significant (P < 0.05) increase in stimulated TNFα in monocytes, compared with NPW.

CONCLUSIONS

Our data confirm that there is an inflammatory reaction in normal pregnancy compared with the non-pregnant state, which may be disrupted during miscarriage.

OBJECTIVE

To investigate differences in body composition and body mass index (BMI) in patients with rheumatoid arthritis (RA) and their correlations with serum production of adiponectin, interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF).

METHODS

The study included 83 patients (age 53±5 years) with RA treated with methotrexate. We determined their BMI, fat mass, and fat-free mass using bioimpedance analysis, and serum concentrations of adiponectin, VEGF, and IL-6 using immunoassay analysis.

RESULTS

Normal BMI was found in 39 (47%), overweight and obesity in 26 (31%), and underweight in 18 (22%) patients. Concentration of adiponectin was lower in overweight/obese patients than in patients with normal BMI (2.1 [0.8-3.9] μg/mL vs 8.9 (7.2-11.3) μg/mL). In underweight patients, it was moderately increased (12.7 [9.3-14.8] μg/mL) and the correlation between the concentrations of adiponectin and IL-6 was positive (r=0.4; P=0.01). Concentrations of VEGF and IL-6 were increased in all groups with RA. The overweight/obese group showed a negative correlation between the concentrations of adiponectin and VEGF (r=- 0.34; P=0.04), a positive correlation between VEGF concentration and fat mass (r=0.39; P=0.02), and a negative correlation between adiponectin concentration and fat mass (r=- 0.23; P=0.02).

CONCLUSIONS

Inflammatory and angiogenesis activation was found in RA patients with all types of body composition, but only in those with obesity and overweight there was a direct antagonism between adiponectin and VEGF. Further research is needed to identify possible regimens of metabolic correction in different variations of body composition.

<AbstractText>There are only limited treatment options for patients with non-cystic fibrosis bronchiectasis (non-CF BE). Human neutrophil elastase (HNE) is a mediator of tissue destruction in non-CF BE. BAY 85-8501, a selective and reversible HNE inhibitor, could represent a new treatment option for this disease.</AbstractText><AbstractText>This was a phase 2a, randomized, placebo-controlled, double-blind, parallel-group study. The primary objective was to assess the safety and tolerability of 1 mg BAY 85-8501 once daily (OD) for 28 days compared with placebo in patients with non-CF BE. Secondary objectives were to investigate the effects of 4 weeks of treatment with BAY 85-8501 on health-related quality of life, pulmonary function, and inflammatory and tissue damage biomarkers in sputum, blood and/or urine, and to evaluate the pharmacokinetics of BAY 85-8501.</AbstractText><AbstractText>Overall, 94 patients (mean age, 66 years; 53% male) were randomized (n = 47 per group), and 82 completed the study (BAY 85-8501, n = 37; placebo, n = 45). Treatment-emergent adverse events (TEAEs) occurred in <em>31</em> patients (66%) taking BAY 85-8501 and in 36 patients (77%) taking placebo, and were mostly mild or moderate. The serious TEAEs (BAY 85-8501, n = 3; placebo, n = 1) were not considered to be study-drug related. There were no changes in pulmonary function parameters from baseline to end of treatment, and health-related quality of life did not improve in any group. HNE activity in blood after zymosan challenge decreased significantly with BAY 85-8501 treatment (P = 0.0250 versus placebo). There were no significant differences in other biomarkers between treatment groups, with the exception of a small increase in <em>interleukin</em>-8 levels in sputum in the BAY 85-8501 group. Trough plasma concentrations of BAY 85-8501 plateaued after 2 weeks.</AbstractText><AbstractText>1 mg BAY 85-8501 OD had a favourable safety and tolerability profile when administered for 28 days to patients with non-CF BE. Further studies with a longer treatment duration are needed to evaluate the potential clinical efficacy in this study population.</AbstractText>

OBJECTIVE

To determine whether interleukin-6 (IL-6) stimulates rat muscle satellite cell proliferation in culture, and if so, to clarify the signalling mechanisms.

METHODS

Primary satellite cells were isolated from thirty male F344 rats, 11 weeks of age. IL-6 at concentrations of 0.01, 0.1, 1, 10 or 100 ng/ml was added to culture media.

RESULTS

IL-6 at 0.01-1 ng/ml induced dose-dependent increase in cell proliferation. After treatment with 1 ng/ml IL-6, cell proliferation increased by 31%, and p-STAT3(+) /MyoD(+) cells increased in number compared to those in control media (P < 0.05). Inhibitors of JAK2 (AG 490) and STAT3 (STAT3 peptide) blocked the increase in BrdUrd(+) cell numbers at 6 h post stimulation with 1 ng/ml IL-6 (P < 0.05). Furthermore, cyclin D1 mRNA expression and cyclin D1(+) /MyoD(+) cell numbers significantly increased in cultures treated with 1 ng/ml IL-6 compared to those in control media (P < 0.05). In contrast, treatment with 10 and 100 ng/ml IL-6 did not stimulate cell proliferation. Treatment with 10 ng/ml IL-6 induced greater SOCS3 mRNA expression than with 1 ng/ml IL-6 and control media. Moreover, co-localization of SOCS3 and myogenin was observed after treatment with 10 ng/ml IL-6.

CONCLUSIONS

IL-6 induced dose-dependent increase in satellite cell proliferation by activating the JAK2/STAT3/cyclin D1 pathway.

BACKGROUND

Low plasma levels of high-density lipoprotein-cholesterol (HDL-C) are typical of acute myocardial infarction (MI) and predict risk of recurrent cardiovascular events. The potential relationships between modifications in the molecular composition and the functionality of HDL subpopulations in acute MI however remain indeterminate.

RESULTS

ST segment elevation MI (STEMI) patients were recruited within 24h after diagnosis (n=16) and featured low HDL-C (-<em>31</em>%, p<0.05) and acute-phase inflammation (determined as marked elevations in C-reactive protein, serum amyloid A (SAA) and <em>interleukin</em>-6) as compared to age- and sex-matched controls (n=10). STEMI plasma HDL and its subpopulations (HDL2b, 2a, 3a, 3b, 3c) displayed attenuated cholesterol efflux capacity from THP-1 cells (up to -32%, p<0.01, on a unit phospholipid mass basis) vs.

METHODS

Plasma HDL and small, dense HDL3b and 3c subpopulations from STEMI patients exhibited reduced anti-oxidative activity (up to -68%, p<0.05, on a unit HDL mass basis). HDL subpopulations in STEMI were enriched in two proinflammatory bioactive lipids, lysophosphatidylcholine (up to 3.0-fold, p<0.05) and phosphatidic acid (up to 8.4-fold, p<0.05), depleted in apolipoprotein A-I (up to -23%, p<0.05) and enriched in SAA (up to +10.2-fold, p<0.05); such changes were most marked in the HDL3b subfraction. In vitro HDL enrichment in both lysophosphatidylcholine and phosphatidic acid exerted deleterious effects on HDL functionality.

CONCLUSIONS

In the early phase of STEMI, HDL particle subpopulations display marked, concomitant alterations in both lipidome and proteome which are implicated in impaired HDL functionality. Such modifications may act synergistically to confer novel deleterious biological activities to STEMI HDL.

CONCLUSIONS

Our present data highlight complex changes in the molecular composition and functionality of HDL particle subpopulations in the acute phase of STEMI, and for the first time, reveal that concomitant modifications in both the lipidome and proteome contribute to functional deficiencies in cholesterol efflux and antioxidative activities of HDL particles. These findings may provide new biomarkers and new insights in therapeutic strategy to reduce cardiovascular risk in this clinical setting where such net deficiency in HDL function, multiplied by low circulating HDL concentrations, can be expected to contribute to accelerated atherogenesis.

The pathogenesis of acute and chronic >> 6 weeks duration) pruritus is complex and involves in the skin a network of resident cells (e. g., mast cells, keratinocytes, sensory neurons) and transient inflammatory cells (e. g., eosinophils). Though pruritus and pain show overlapping mechanisms, recent studies have provided evidence that pruritus and pain pathogenesis differ in important points. In the skin, the sensory C-nerve fibers have been investigated intensively. Several classes of histamine-sensitive or histamine-insensitve C-fibers have been described. Epidermal and dermal sensory nerve fibres are now assumed to be of major importance in pruritus induction. They interact with keratinocytes, inflammatory cells such as T lymphocytes, eosinophils and basophils which have been shown to release multiple pruritogenic mediators (e.g., nerve growth factor, <em>interleukin</em>-<em>31</em>) which lead to activation, sensitization and sprouting of skin nerves. Specific receptors have been discovered on cutaneous and spinal neurons to be exclusively involved in the processing of pruritic signals. Just recently, the gastrin-releasing peptide receptor (GRPR) was identified on spinal neurons that are crucially involved in pruritus but not pain processing. Chronic pruritus is notoriously difficult to treat. Newer insights into the underlying pathogenesis of pruritus have enabled novel treatment approaches that target the pruritus-specific pathophysiological mechanism. For example, kappa-opioid receptor agonists and neurokinin-1 antagonists have been found to relieve chronic pruritus.

BACKGROUND

Scrub typhus, caused by Orientia tsutsugamushi, is endemic in the Asia-Pacific region. Mortality is high if untreated, and even with treatment as high as 10-20%, further knowledge of the immune response during scrub typhus is needed. The current study was aimed at comparing plasma levels of a variety of inflammatory mediators in scrub typhus patients and controls in South India in order to map the broader cytokine profile and their relation to disease severity and clinical outcome.

RESULTS

We examined plasma levels of several cytokines in scrub typhus patients (n = 129) compared to healthy controls (n = <em>31</em>) and infectious disease controls (n = <em>31</em>), both in the acute phase and after recovery, by multiplex technology and enzyme immunoassays. Scrub typhus patients were characterized by marked changes in the cytokine network during the acute phase, differing not only from healthy controls but also from infectious disease controls. While most of the inflammatory markers were raised in scrub typhus, platelet-derived mediators such as RANTES were markedly decreased, probably reflecting enhanced platelet activation. Some of the inflammatory markers, including various chemokines (e.g., <em>interleukin</em>-8, monocyte chemoattractant peptide-1 and macrophage inflammatory protein-1β) and downstream markers of inflammation (e.g., C-reactive protein and pentraxin-3), were also associated with disease severity and mortality during follow-up, with a particular strong association with <em>interleukin</em>-8.

CONCLUSIONS

Our findings suggest that scrub typhus is characterized by a certain cytokine profile that includes dysregulated levels of a wide range of mediators, and that this enhanced inflammation could contribute to disease severity and clinical outcome.

Background: Interleukin-1 has been implicated as a mediator of recurrent pericarditis. The efficacy and safety of rilonacept, an interleukin-1α and interleukin-1β cytokine trap, were studied previously in a phase 2 trial involving patients with recurrent pericarditis.

Methods: We conducted a phase 3, multicenter, double-blind, event-driven, randomized-withdrawal trial of rilonacept in patients with acute symptoms of recurrent pericarditis (as assessed on a patient-reported scale) and systemic inflammation (as shown by an elevated C-reactive protein [CRP] level). Patients presenting with pericarditis recurrence while receiving standard therapy were enrolled in a 12-week run-in period, during which rilonacept was initiated and background medications were discontinued. Patients who had a clinical response (i.e., met prespecified response criteria) were randomly assigned in a 1:1 ratio to receive continued rilonacept monotherapy or placebo, administered subcutaneously once weekly. The primary efficacy end point, assessed with a Cox proportional-hazards model, was the time to the first pericarditis recurrence. Safety was also assessed.

Results: A total of 86 patients with pericarditis pain and an elevated CRP level were enrolled in the run-in period. During the run-in period, the median time to resolution or near-resolution of pain was 5 days, and the median time to normalization of the CRP level was 7 days. A total of 61 patients underwent randomization. During the randomized-withdrawal period, there were too few recurrence events in the rilonacept group to allow for the median time to the first adjudicated recurrence to be calculated; the median time to the first adjudicated recurrence in the placebo group was 8.6 weeks (95% confidence interval [CI], 4.0 to 11.7; hazard ratio in a Cox proportional-hazards model, 0.04; 95% CI, 0.01 to 0.18; P<0.001 by the log-rank test). During this period, 2 of 30 patients (7%) in the rilonacept group had a pericarditis recurrence, as compared with 23 of 31 patients (74%) in the placebo group. In the run-in period, 4 patients had adverse events leading to the discontinuation of rilonacept therapy. The most common adverse events with rilonacept were injection-site reactions and upper respiratory tract infections.

Conclusions: Among patients with recurrent pericarditis, rilonacept led to rapid resolution of recurrent pericarditis episodes and to a significantly lower risk of pericarditis recurrence than placebo. (Funded by Kiniksa Pharmaceuticals; RHAPSODY ClinicalTrials.gov number, NCT03737110.).

In an effort to develop a biochemotherapy regimen for metastatic melanoma suitable for testing in a cooperative group setting, we modified the concurrent biochemotherapy regimen of S. S. Legha et al. (J. Clin. Oncol., 16: 1752-1759, 1998) by providing enhanced supportive care and developing a strict, conservative approach to the management of treatment-related toxicities. Patients received cisplatin, vinblastine, and dacarbazine (CVD: cisplatin (20 mg/m2) and vinblastine (1.2 mg/m2) on days 1-4, dacarbazine (800 mg/m2) on day 1 only) concurrently with <em>interleukin</em> 2 (9 MIU/m2/day) by continuous i.v. infusion on days 1-4 and IFN-alpha (5 MU/m2/day) on days 1-5, 8, 10, and 12. Prophylactic antibiotics and a maximum of four cycles were administered. Routine granulocyte colony-stimulating factor and aggressive antiemetics were initiated after patients 7 and 14, respectively. Forty-four patients were enrolled in this study. No patients had received prior chemotherapy or <em>interleukin</em> 2; however, 23 (53%) had received prior IFN-alpha, mostly in the adjuvant setting. A total of 1<em>31</em> treatment cycles was administered. Significant toxicities requiring dose modification included: hypotension requiring pressors (15 episodes in 11 patients), grades 3/4 vomiting (12 episodes in 15 cycles; 5 episodes in 12 patients (6 episodes in 9 cycles after initiation of the modified antiemetic regimen), transient renal insufficiency (5 episodes in 5 patients), grade 4 thrombocytopenia (24 episodes, 1 associated with bleeding), neutropenia with or without fever (15 instances, only 11 in 112 cycles after routine use of granulocyte colony-stimulating factor), and catheter-related bacteremia (2 patients). Five (16%) of 30 patients who were treated after the last protocol modification experienced what we defined as unacceptable toxicity for a cooperative group setting. Responses were seen in 19 of 40 evaluable patients (relative risk, 48%) with 8 complete responses (20%). The median response duration was 7 months (range, 1-17+ months) with one currently ongoing. The central nervous system was the initial site of relapse in 11 responding patients. The median survival duration was 11 months (range, 2-<em>31</em> months). This modified, concurrent biochemotherapy regimen is active and tolerable for use in a cooperative group setting. Central nervous system relapse, however, remains a concern for responders. This regimen is being compared with CVD in a Phase III Intergroup Trial (Eastern Cooperative Oncology Group/Southwest Oncology Group 3695).

BACKGROUND

Several inflammatory cytokines play a key part in the induction of osteoporosis. Until now, involvement of the Th2 cytokine <em>interleukin</em>-<em>31</em> (IL-<em>31</em>) in osteoporosis hadn't yet been studied. IL-<em>31</em> is a proinflammatory cytokine mediating multiple immune functions, whose involvement in a wide range of diseases, such as atopic dermatitis, inflammatory bowel diseases and cutaneous lymphomas, is now emerging. Given the important role of IL-<em>31</em> in inflammation, we measured its serum levels in postmenopausal osteoporotic patients.

RESULTS

In fifty-six postmenopausal females with osteoporosis and 26 healthy controls, bone mineral density (BMD) measurements were performed by using calcaneal quantitative ultrasound (QUS) technique, confirmed at the lumbar spine and hip by dual energy X-ray absorptiometry (DXA). Both patients and controls were divided according to age (less or more than 65 years) and disease severity (T-score levels and presence of fractures). Serum IL-<em>31</em> levels were measured by ELISA technique. Osteoporotic patients exhibited elevated levels of serum IL-<em>31</em> compared with healthy controls (43.12 ± 6.97 vs 29.58 ± 6.09 pg/ml; p < 0.049). IL-<em>31</em> expression was higher in over 65 years old patients compared to age-matched controls (45 ± 11.05 vs. 17.92 ± 5.92; p < 0.01), whereas in younger subjects no statistically significant differences were detected between patients and controls (37.91 ± 6.9 vs 32.08 ± 8.2). No statistically significant differences were found between IL-<em>31</em> levels in patients affected by mild (T-score>> -3) compared to severe (T-score < -3) osteoporosis (59.17 ± 9.22 vs 37.91 ± 10.52), neither between fractured and unfractured osteoporotic women (33.75 ± 9.16 vs 51.25 ± 8.9).

CONCLUSIONS

We showed for the first time an increase of IL-<em>31</em> serum levels in postmenopausal women with decreased BMD. Although they did not reflect the severity of osteoporosis and/or the presence of fractures, they clearly correlated with age, as reflected by the higher levels of this cytokine in aged patients.

BACKGROUND

Inflammation is a major contributor to atherosclerotic vascular disease. Inflammatory parameters such as C-reactive protein (CRP) and Interleukin-6 (IL-6) have been shown to be strong predictors of cardiovascular events. The association between preoperative inflammatory parameters and early graft occlusion as well as cardiovascular events after coronary artery bypass grafting (CABG) has not, however, been fully elucidated. The aims of the present study were to prospectively investigate the prognostic value of the inflammatory parameters IL-6, CRP, and endothelin (ET-1) to predict early graft occlusion as well as late cardiovascular events after CABG.

METHODS

In the present study 99 patients undergoing CABG because of stable angina pectoris due to significant coronary artery disease were prospectively included. Coronary angiography was repeated 3 months after CABG in 81 patients in order to evaluate early graft occlusion. Blood samples were collected before CABG in all patients. Patients were followed up for a median of 5 (3-7) years after CABG.

RESULTS

Twenty-five patients (31%) had one or more occluded grafts at the 3-month control coronary angiography. The patients with occluded grafts had higher preoperative CRP and IL-6 levels in plasma [CRP 2.22 (1.11-4.47) mg/L vs. 1.23 (0.71-2.27) mg/L P=0.03] and [IL-6 2.88 (1.91-5.94) pg/mL vs. 2.15 (1.54-3.14) pg/mL P=0.006]. There were 23 late cardiovascular events among the 99 patients during the follow-up. Patients experiencing late cardiovascular events had higher preoperative IL-6 levels than those without late cardiovascular events [4.13 (1.83-5.87) pg/mL vs. 2.08 (1.53-2.29) pg/mL, P=0.002] whereas CRP levels did not differ significantly between the two groups [1.5 (0.79-4.41) mg/L vs. 1.33 (0.74-2.48) mg/L, P=0.41]. Looking at IL-6, a cut off value more than 3.8 pg/ml was associated with a significant higher risk for an early graft occlusion (P=0.04) and late cardiovascular events (P=0.00003). Preoperative endothelin-1 did not predict early graft occlusions or late cardiovascular events.

CONCLUSIONS

Raised preoperative IL-6 levels are predictors of both early graft occlusion and late cardiovascular events after CABG. Elevated preoperative CRP levels can predict early graft occlusion after CABG. Endothelin did not differ between the two groups.

OBJECTIVE

To determine whether the administration of anticytokine agents, the interleukin-1 receptor antagonist (IL-1ra) and a soluble tumor necrosis factor receptor Fc fusion protein (sTNFR-Fc), prevents endotoxin-induced preterm delivery in mice.

METHODS

C3H/HeN pregnant mice at 15 days of gestation (70% gestation) were randomized to receive phosphate-buffered saline (PBS) or lipopolysaccharide (LPS) (50 micrograms/mouse) intraperitoneally (i.p.). Randomly selected PBS- or LPS-treated mice were additionally treated intravenously (i.v.), i.p., or subcutaneously (s.c.) every 3 hours with IL-1ra (1-50 mg) or every 12 hours with sTNFR-Fc (200-400 micrograms) beginning 1 hour before LPS injection. Animals were observed for vaginal bleeding and preterm delivery.

RESULTS

Mice treated i.p. with 50 micrograms LPS (n = 13) had a shorter injection-to-delivery interval than mice treated similarly with PBS (n = 19) (median 13.5 hours, range 10-105 versus median 86.8 hours, range 53-120, respectively; P < .001). Saline-treated mice given 10 mg IL-1ra every 3 hours i.p. (n = 3) or 200 micrograms sTNFR-Fc every 12 hours i.v. (n = 4) had similar injection-to-delivery intervals as PBS-treated control mice (median 70 hours, range 70-76 versus median 58 hours, range 50-120, respectively). Similarly, LPS-treated mice given PBS every 3 hours (n = 20) had injection-to-delivery intervals comparable to LPS-treated mice (n = 13) (median 15.5 hours, range 9.8-92 versus median 13.5 hours, range 10-105, respectively). Lipopolysaccharide-treated mice given i.p. injections of 1 (n = 4), 10 (n = 31), or 50 (n = 15) mg of IL-1ra every 3 hours did not have longer injection-to-delivery intervals compared with LPS-treated mice (n = 13) (medians 11.6, 15, 14.5 and 13.5 hours; ranges 10.8-12, 8-95, 11-92, and 10-105, respectively). Lipopolysaccharide-treated mice given i.v. injections of 200 (n = 4) or 400 (n = 9) micrograms sTNFR-Fc every 12 hours did not have longer injection-to-delivery intervals compared with LPS-treated mice (n = 8) (medians 23.3, 22.5, and 21.9 hours; ranges 14.8-33, 15-95.5, and 15.5-44, respectively). The median injection-to-delivery interval of LPS-treated mice given both IL-1ra (10 mg) every 3 hours i.p. and sTNFR-Fc (200 micrograms) every 12 hours i.v. (n = 5) was not different from that of LPS-treated mice (median 26 hours, range 24.5-72 versus median 13.5 hours, range 10-105, respectively; P>> .05).

CONCLUSIONS

The anticytokine agents IL-1ra and sTNFR-Fc did not prevent preterm delivery or prolong pregnancy in endotoxin-induced preterm labor in mice.

BACKGROUND

Pim1 overexpression was found to be associated with more advanced prostate cancer. Interleukin-6 (IL-6) induces Pim1 expression and is often found elevated after androgen-ablative therapy.

METHODS

Tumor tissue from 31 selected prostate cancer patients and cell lines were studied immunohistochemically for c-myc, Pim1, STAT3, pSTAT3-Tyr705, and androgen receptor (AR) expression. The effect of Pim1 on androgen dependence in prostate cancer was studied in transgene cell lines.

RESULTS

Pim1 expression was increased in high-grade prostate tumors (Gleason >7), irrespective of androgen status, was highest in hormone refractory prostate cancer and correlated to pSTAT3-Tyr705 expression levels. Co-expression of Pim1 and MYC was observed specifically after androgen ablation. Pim1 expression could be induced in LNCaP and PC3 cells by IL-6. Pim1 overexpression in PC3 and PNCaP increased the transcriptional activity of the AR at low levels of dihydrotestosterone. Consequently, Pim1 expression increased LNCaP cell survival specifically at castrate levels of androgen.

CONCLUSIONS

Pim1 expression was increased in primary tumor samples after androgen ablation. Pim1 overexpression increased AR transcriptional activity in a ligand-dependent manner in prostate cancer cell lines, resulting in enhanced cell survival at castrate levels of androgen.

BACKGROUND

<em>Interleukin</em> <em>31</em> (IL-<em>31</em>) is a T helper type 2 effector cytokine that plays an important role in the pathogenesis of atopic and allergic diseases. IL-<em>31</em> may be involved in promoting allergic inflammation and in inducing airway epithelial responses such as allergic asthma.

METHODS

Single-base extension analysis was used to detect the genotypes of IL-<em>31</em> single nucleotide polymorphisms (SNPs), and we compared the genotype and allele frequencies of the IL-<em>31</em> SNPs between patients with asthma and healthy controls.

RESULTS

There were no significant differences in the genotype and allele frequencies of the IL-<em>31</em> SNPs between patients with asthma and healthy controls. Furthermore we compared the genotype and allele frequencies of IL-<em>31</em> SNPs between patients with atopic asthma, those with non-atopic asthma and healthy controls. This showed that the SNPs were not associated with the susceptibility to atopic asthma. There were no significant differences in the haplotype frequencies of IL-<em>31</em> SNPs between patients with asthma and healthy controls. In patients with asthma, the IL-<em>31</em> SNPs were significantly correlated with total serum levels of IgE (p=0.035).

CONCLUSIONS

Our results indicate that, the IL-<em>31</em> SNPs may be associated with IgE production in patients with asthma.

OBJECTIVE

The aim of this study was to investigate and compare the clinical, microbial, and inflammatory effects of a diode laser as an adjunct to scaling and root planing (SRP) versus SRP alone for the treatment of generalized aggressive periodontitis (GAgP).

METHODS

Using a split-mouth design, <em>31</em> patients with GAgP were enrolled in the study. The maxillary right and left quadrants were randomly assigned to SRP+diode laser or SRP alone. Patients were examined on a regular basis for clinical, microbiological, and inflammatory mediator changes over a 1-year period. Clinical attachment level (CAL) was the primary outcome variable chosen. In addition, subgingival biofilm samples and gingival crevicular fluid (GCF) inflammatory mediators were analyzed at each follow-up session.

RESULTS

Compared to baseline, both treatments demonstrated an improvement in periodontal parameters at 1 year. However, SRP+diode laser produced a significant improvement in probing depth (PD; 2.56 ± 0.44 vs. 3.36 ± 0.51 mm, p < 0.05) and CAL (3.47 ± 0.25 vs. 4.11 ± 0.26 mm, p < 0.05) values compared to SRP alone. Similarly, in the SRP+diode laser group, the bacteria of orange complex group were significantly reduced at 30 and 60 days compared to SRP alone. Moreover, SRP+diode laser determined a reduction in mean GCF level of interleukin (IL)-1β and IL-1β/IL-10 ratio at 15 and 30 days compared to SRP alone (p < 0.05).

CONCLUSIONS

At 1 year, SRP+diode laser yielded a significant reduction in some clinical parameters, while microbial and inflammatory mediator changes were not significantly reduced compared to SRP alone.

Pruritus is one of the cardinal symptoms found in patients with leukemic cutaneous T cell lymphoma (CTCL). The nature of the pruritus experienced by CTCL patients is complex, involving different pathways and cell mediators, thus making it poorly responsive to conventional anti-itch therapies. Recent reports highlight the role of <em>interleukin</em> <em>31</em> (IL-<em>31</em>) as a novel cytokine involved in the pathogenesis of pruritus in atopic dermatitis and CTCL. Here we provide both in vivo and in vitro evidence suggesting that histone deacetylase (HDAC) inhibitors may mitigate itch through lowering of levels of IL-<em>31</em>-expressing T cells. Furthermore, we demonstrate that chemokine receptor type-4 (CCR4)-bearing T cells are a main source of IL-<em>31</em> in CTCL, and that neutralizing the IL-<em>31</em> pathway through targeting of the CCR4-expressing T cells may represent a promising therapeutic strategy for symptomatic relief in CTCL.

The proinflammatory cytokines transforming growth factor beta 1 (TGF-β1) and <em>interleukin</em> (IL)-<em>31</em> have been implicated in tissue injury. However, whether TGF-β1/IL-<em>31</em> are stimulated and elevated in response to liver injury that leads to fibrogenesis in hepatitis B virus-related liver cirrhosis (HBV-LC) remains unclear. To investigate the association between TGF-β1/IL-<em>31</em> and stages of chronic HBV infection, serum TGF-β1, IL-9, IL-10,IL-17, IL-22, IL-23, IL-<em>31</em>, IL-33, and IL-35 were determined among patients with chronic hepatitis B (CHB; n=19), HBV-LC (n=20), and a normal control population (NC; n=18). Disease severity in patients with HBV-LC was assessed using model for end-stage liver disease (MELD) scores. Serum TGF-β1 and IL-<em>31</em> levels were strongly positively linked in all subjects, and both correlated positively with IL-22, IL-33, and IL-17. TGF-β1 and IL-<em>31</em> levels in the blood were both significantly higher in CHB and HBV-LC patients than in NC subjects. Elevated serum TGF-β1 and IL-<em>31</em> levels were positively associated with albumin, alpha-fetoprotein, creatinine, white blood cell count, and platelet levels. Serum TGF-β1 and IL-<em>31</em> were markedly higher in HBV-LC patients who did not have esophageal varices, and IL-<em>31</em> had the highest sensitivity and specificity (90.9% and 66.7%, respectively) for indicating the absence of this complication. In summary, TGF-β1 and IL-<em>31</em> were linked to progression from CHB to LC, and correlated well with the severity of HBV-LC. These findings suggest possible roles of the TGF-β1/IL-<em>31</em> pathway in the pathogenesis of liver fibrosis during chronic HBV infection.

BACKGROUND

Because of deteriorating exocrine function, malabsorption renders chronic pancreatitis (CP) patients at risk of osteoporosis and fracture. However, the pathogenesis of low bone mineral density (BMD) has not been characterized. We hypothesized that bone turnover is elevated in CP, and we sought to investigate an association between bone metabolism and systemic inflammation.

METHODS

Twenty-nine CP patients and twenty-nine matched controls were recruited. Bone-turnover markers procollagen 1 amino-terminal propeptide (P1NP), OC (osteocalcin; bone formation markers), and carboxy-terminal telopeptide of type I collagen (CTX-I; bone resorption marker) were measured along with vitamin D (25-hydroxyvitamin D, 25OHD), parathyroid hormone (PTH), interleukin 6 (IL-6), high-sensitivity (hs) C-reactive protein (CRP), and sex/thyroid hormones. BMD was measured by dual-energy X-ray absorptiometry. Smoking status was noted.

RESULTS

Of the CP patients, 31% had osteoporosis and 44.8% osteopenia (controls: 6.9 and 51.7%, respectively; P=0.019). BMD was lower for patients at the lumbar spine (P=0.014) and femoral neck (P=0.029). Patients had elevated bone formation (P1NP (P=0.0068), OC (P=0.033)) and bone resportion (CTX-I (P=0.016)) compared with controls. Patients had lower 25OHD compared with controls (P=0.0126) and higher inflammatory markers (hsCRP, P=0.0013). Sex and thyroid hormone levels were similar. Patients with lowest 25OHD levels had highest P1NP. In a multivariable model, age, PTH, and smoking were predictive of 25OHD. Patients with osteoporosis had higher P1NP, PTH, and IL-6 and lower 25OHD. Using analysis of variance, inflammation (hsCRP) was highest in those with lowest 25OHD and lowest BMD.

CONCLUSIONS

For the first time, bone turnover was shown to be abnormal in CP, and importantly, an association between low 25-OHD, smoking, and systematic inflammation was identified. Moreover, those with osteoporosis had the highest systemic inflammation. Together these factors provide an avenue for potential modification of risk factors, which may ultimately reduce bone loss and avert fractures in this group.

Cytokine gene polymorphisms modify expression and their circulating protein levels reflect inflammatory response. Chronic inflammation plays a key role in the pathogenesis of colorectal neoplasia (CRN) associated with inflammatory bowel disease, but it is not clear whether inflammation is a cause or an effect of tumours in sporadic CRN. We therefore investigated the association of cytokine gene polymorphisms and circulating cytokine levels on the risk of CRN in Northeast Scotland, which has a high incidence of CRN. We recruited two groups of patients from a screening colonoscopy cohort, either preprocedure or 3-24 months postprocedure. Participants with CRN were compared with participants with no evidence of CRN (controls). Blood-derived DNA was used to genotype polymorphisms in IL1B, IL1-RN, IL6, IL8, IL10, PTGS2 and TNFA genes. Circulating levels of high-sensitivity C-reactive protein and six cytokines [<em>interleukin</em>-1β (IL-1β), IL-4, IL-6, IL-8, IL-10 and tumour necrosis factor-α (TNF-α)] were measured. To examine the effect of CRN resection on marker levels, we used propensity score matching. A total of 884 patients were eligible for analysis, including 388 CRN cases and 496 controls. Cases were older (mean age 64 vs. 62 years, P<0.01) and more likely to be men (67 vs. 55%, P<0.001). Controls were more likely to be regular users of NSAID (P<0.0001). Compared with homozygous carriage of respective common alleles, proinflammatory CC genotypes of IL1B-<em>31</em>C>T [odds ratio (OR) (95% confidence interval (CI) 1.68 (1.03-2.73)] and PTGS2-765 C>G [OR (95% CI) 2.97 (1.05-8.46)] were each associated with an increased risk of CRN. Conversely, carriage of the A allele of IL8-251A>T was associated with a lower risk of CRN compared with the TT genotype [ORs (95% CI) 0.60 (0.41-0.86) for heterozygous, 0.88 (0.57-1.37) for homozygous, and 0.68 (0.48-0.95) for heterozygous and homozygous combined]. Compared with postprocedure cases, IL8, TNF-α and C-reactive protein levels were significantly higher in preprocedure cases, but IL4 and IL10 protein levels were significantly lower. Proinflammatory cytokine gene polymorphisms in IL1B-<em>31</em> and PTGS2-765 increase the risk of developing CRN. Levels of proinflammatory IL8, TNF-α and C-reactive protein markers are significantly higher while CRN is in situ. Along with the NSAID findings, these data point to inflammation as an underlying pathogenetic mechanism in CRN.

Acute psychosocial stress stimulates transient increases in circulating pro-inflammatory plasma cytokines, but little is known about stress effects on anti-inflammatory cytokines or underlying mechanisms. We investigated the stress kinetics and interrelations of pro- and anti-inflammatory measures on the transcriptional and protein level. Forty-five healthy men were randomly assigned to either a stress or control group. While the stress group underwent an acute psychosocial stress task, the second group participated in a non-stress control condition. We repeatedly measured before and up to 120min after stress DNA binding activity of the pro-inflammatory transcription factor NF-κB (NF-κB-BA) in peripheral blood mononuclear cells, whole-blood mRNA levels of NF-κB, its inhibitor IκBα, and of the pro-inflammatory cytokines <em>interleukin</em> (IL)-1ß and IL-6, and the anti-inflammatory cytokine IL-10. We also repeatedly measured plasma levels of IL-1ß, IL-6, and IL-10. Compared to non-stress, acute stress induced significant and rapid increases in NF-κB-BA and delayed increases in plasma IL-6 and mRNA of IL-1ß, IL-6, and IκBα (p's<.045). In the stress group, significant increases over time were also observed for NF-κB mRNA and plasma IL-1ß and IL-10 (p's<.055). NF-κB-BA correlated significantly with mRNA of IL-1β (r=.52, p=.002), NF-κB (r=.48, p=.004), and IκBα (r=.42, p=.013), and marginally with IL-6 mRNA (r=.<em>31</em>, p=.11). Plasma cytokines did not relate to NF-κB-BA or mRNA levels of the respective cytokines. Our data suggest that stress induces increases in NF-κB-BA that relate to subsequent mRNA expression of pro-inflammatory, but not anti-inflammatory cytokines, and of regulatory-cytoplasmic-proteins. The stress-induced increases in plasma cytokines do not seem to derive from de novo synthesis in circulating blood cells.

We sought to identify novel urinary biomarkers of kidney function in type 2 diabetes. We screened the renal transcriptome of db/db and db/m mice for differentially expressed mRNA transcripts that encode secreted proteins with human orthologs. Whether elevated urine levels of the orthologous proteins correlated with diminished glomerular filtration rate was tested in a cross-sectional study of n = 56 patients with type 2 diabetes. We identified 36 putative biomarker genes in db/db kidneys: <em>31</em> upregulated and 5 downregulated. Urinary protein levels of six selected candidates (endothelin-1, lipocalin-2, transforming growth factor-β, growth and differentiation factor-15, <em>interleukin</em>-6, and macrophage chemoattractant protein-1) were elevated in type 2 diabetic patients with subnormal glomerular filtration rate (i.e., <90 ml·min(-1)·1.73 m(-2)), independent of microalbuminuria, age, sex, race, and use of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists. In contrast, urinary levels of fibroblast growth factor were not increased. A composite variable of urine albumin and any of the six candidate markers was associated with subnormal estimated glomerular filtration rate more closely than albumin alone. In addition, urinary endothelin-1, growth and differentiation factor-15, and <em>interleukin</em>-6 were associated with a marker of proximal tubule damage, N-acetyl-β-d-glucosaminidase activity. These results suggest that gene expression profiling in diabetic mouse kidney can complement existing proteomic-based approaches for renal biomarker discovery in humans.

BACKGROUND

The objective of this study was to measure associations of circulating interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) levels with anthropometric and abdominal fat distribution in overweight or obese postmenopausal women.

METHODS

One hundred eight overweight or obese postmenopausal were evaluated. Demographic and anthropometric measurements were done. Serum IL-6, TNF-alpha, glucose, and insulin levels were measured. Insulin resistance was calculated by using homeostasis model assessment-insulin resistance (HOMA-IR). The assessment of abdominal fat distribution was performed by ultrasonography. Statistical analysis was made with Pearson and partial correlation analysis.

RESULTS

There was a positive correlation between serum IL-6 and TNF-alpha (r = .19; p = .047). IL-6 was positively correlated with body mass index (BMI) (r = .43; p = .0001), waist circumference (r = .41; p = .0001), and visceral fat layer (r = .33; p = .0001) measurements and HOMA-IR index (r = .31, p = .001). A positive relationship between HOMA-IR and visceral fat layer thickness was observed (r = .320; p = .0001). TNF-alpha was positively associated with BMI but not with any measures of central obesity. When adjustment for BMI was performed, there were no significant relationships between the studied parameters.

CONCLUSIONS

There are no significant correlations between abdominal fat distributions measured by ultrasonography and circulating IL-6 and TNF-alpha levels. BMI may have a stronger association with circulating inflammatory cytokine concentrations than with different measures of central obesity in overweight or obese postmenopausal women.

BACKGROUND

Statins may provide additional benefits in patients with cardiac failure due to their pleiotropic effects besides their cholesterol-lowering actions. In this study, we aimed to evaluate the impact of 12-week fluvastatin therapy on the inflammatory cytokines and the ventricular performance markers in patients with heart failure.

RESULTS

Fourty chronic heart failure patients, twenty with idiopathic dilated cardiomyopathy (DCM group) and 20 with ischemic cardiomyopathy (ICM group), for whom statin treatment was indicated according to Adult Treatment Panel III were included to this open label and prospective study. After a 12-week treatment with fluvastatin 80 mg/day; clinical functional capacity, echocardiographic indices of cardiac performance and inflammatory markers were evaluated. After the treatment, functional capacity (in DCM group: 2.05+/-0.4 versus 1.65+/-0.6, p=0.005; in ICM group: 2.25+/-0.5 versus 1.8+/-0.6, p=0.003), left ventricular ejection fraction, LVEF (from 30+/-5% to 33+/-5%, p=0.001 in DCM and 29+/-4% to <em>31</em>+/-5%, p=0.001 in ICM group) and tissue Doppler mitral annular systolic velocity, Sm (5.8+/-1 cm/s to 7+/-1 cm/s, p=0.001 in DCM and 5.4+/-0.8 cm/s to 7+/-1 cm/s, p=0.001 in ICM group) improved. Tumor necrosis factor-alpha and <em>interleukin</em>-6 levels decreased, but no significant changes in high sensitive C-reactive protein and brain natriuretic peptide levels were detected with the fluvastatin treatment in both groups.

CONCLUSIONS

Fluvastatin improved cardiac functions and the clinical symptoms in HF patients with either idiopathic dilated or ischemic etiology. This positive effect of fluvastatin which might be secondary to inflammatory modulation was more marked in patients with ischemic etiology. Statins in HF deserves special attention by means of further large-scale trials.