The fast reaction of the actin-based cytoskeleton in motile cells after stimulation with a chemoattractant requires a signal-transduction chain that creates a very specific environment at distinct regions beneath the plasma membrane. Dictyostelium hisactophilin, a unique actin-binding protein, is a submembranous pH sensor that signals slight changes of the H+ concentration to actin by inducing actin polymerization and binding to microfilaments only at pH values below seven. It has a relative molecular mass of 13.5K and its most unusual feature is the presence of <em>31</em> histidine residues among its total of 118 amino acids. The transduction of an external signal from the plasma membrane to the cytoskeleton is poorly understood. Here we report the protein's structure in solution determined by nuclear magnetic resonance spectroscopy. The nuclear Overhauser effect intensities of the three-dimensional nuclear Overhauser spectra were used directly in the calculations. The overall folding of histactophilin is similar to that of <em>interleukin</em>-1 beta and fibroblast growth factor, but the primary amino-acid sequence of hisactophilin is unrelated to these two proteins.

To understand the secretion and processing of <em>interleukin</em>-1 (IL-1), a Chinese hamster fibroblast cell line (R1610) was transfected with a human IL-1 beta cDNA under the control of the SV40 early promoter and linked to the gene for neomycin resistance. After selecting for transfected cells resistant to G418, two clones were found to constitutively express the IL-1 beta <em>31</em>-kD precursor which was almost exclusively located in the cytosol. Pulse-chase experiments failed to show any secretion of IL-1 and very little IL-1 activity was detectable in cell supernatants. Furthermore, surface membrane IL-1 activity could not be detected, although low levels of activity could be released upon brief trypsin treatment. Therefore, unlike monocytes, these fibroblast cells lack the mechanism for secreting and processing of IL-1 beta.

BACKGROUND

Obstructive sleep apnea (OSA) is characterized by recurrent nocturnal hypoxia and sleep disruption. Sleep fragmentation caused hyperalgesia in volunteers, while nocturnal hypoxemia enhanced morphine analgesic potency in children with OSA. This evidence directly relates to surgical OSA patients who are at risk for airway compromise due to postoperative use of opioids. Using accepted experimental pain models, we characterized pain processing and opioid analgesia in male volunteers recruited based on their risk for OSA.

METHODS

After approval from the Intitutional Review Board and informed consent, we assessed heat and cold pain thresholds and tolerances in volunteers after overnight polysomnography (PSG). Three pro-inflammatory and 3 hypoxia markers were determined in the serum. Pain tests were performed at baseline, placebo, and two effect site concentrations of remifentanil (1 and 2 µg/ml), an μ-opioid agonist. Linear mixed effects regression models were employed to evaluate the association of 3 PSG descriptors [wake after sleep onset, number of sleep stage shifts, and lowest oxyhemoglobin saturation (SaO(2)) during sleep] and all serum markers with pain thresholds and tolerances at baseline, as well as their changes under remifentanil.

RESULTS

Forty-three volunteers (12 normal and <em>31</em> with a PSG-based diagnosis of OSA) were included in the analysis. The lower nadir SaO(2) and higher insulin growth factor binding protein-1 (IGFBP-1) were associated with higher analgesic sensitivity to remifentanil (SaO(2), P = 0.0440; IGFBP-1, P = 0.0013). Other pro-inflammatory mediators like <em>interleukin</em>-1β and tumor necrosis factor-α (TNF-α) were associated with an enhanced sensitivity to the opioid analgesic effect (IL-1β, P = 0.0218; TNF-α, P = 0.0276).

CONCLUSIONS

Nocturnal hypoxemia in subjects at high risk for OSA was associated with an increased potency of opioid analgesia. A serum hypoxia marker (IGFBP-1) was associated with hypoalgesia and increased potency to opioid analgesia; other pro-inflammatory mediators also predicted an enhanced opioid potency.

BACKGROUND

Clinicaltrials.gov NCT00672737.

The matrix metalloproteinases (MMPs) collagenase, gelatinase and stromelysin, contribute to the destruction of articular cartilage which occurs during rheumatoid and osteoarthritis. Ro <em>31</em>-4724, a substrate analogue containing a hydroxamic acid function, is a potent but non-selective inhibitor of all three MMPs (I50, collagenase = 10 nM), whereas Ro <em>31</em>-7467, a phosphinic acid transition-state analogue, shows 14-fold and 12-fold selectivity for collagenase (I50 = 17 nM) over gelatinase and caseinase (stromelysin) respectively. The effects of these inhibitors on <em>interleukin</em>-1-induced bovine nasal cartilage degradation were examined. The hydroxamate Ro <em>31</em>-4724 inhibits proteoglycan and collagen loss, whereas the phosphinic acid Ro <em>31</em>-7467 selectively inhibits collagen breakdown in this model. This represents the first demonstration of potent and selective inhibition of IL1-induced cartilage degradation in vitro by MMP inhibitors. These results suggest that collagenase is responsible for collagen loss and that a different enzyme, possibly stromelysin, is responsible for proteoglycan degradation in this model.

Ovarian cancer patients with persistent (platinum-resistant) or progressive (platinum-refractory) disease respond poorly to second line chemotherapy and have low survival expectancy. New and improved therapeutic approaches are needed and immune biologics are one possibility. <em>Interleukin</em>-2 (IL-2) is a T-cell growth factor believed to be important in anti-tumor immunity. We performed a phase II clinical trial with intraperitoneal (IP) recombinant IL-2 administered in weekly infusions of 6 x 10(5) IU/m2. Thirty-one subjects were sequentially entered into the study and clinical responses were surgically confirmed in 24 patients. The primary end point of this study was clinical response with immunologic measurements as secondary end points. The IP regimen was generally well tolerated. Of the 24 patients assessed for response, there were 6 (4 complete, 2 partial) responses for an overall response rate of 25.0% [95% confidence interval (CI) of 11-45]. The median survival of the <em>31</em> patient cohort was 2.1 years (95% CI of 1.3-4.4), but for the 6 patients with responses the median survival has not been reached (range 24-120+ months). Eosinophil and lymphocyte numbers were continuously monitored during treatment. Peripheral blood eosinophils were markedly increased at the completion of treatment (p < 0.0001) and associated with increased circulating eotaxin (p = 0.03). We also found significant associations between changes in CD3 counts and survival (p = 0.05) and between IFNγ- secreting CD8 T cells at early time points and survival (p = 0.04). This study provides important evidence for IP IL-2 in platinum-resistant ovarian cancer and identifies several immune correlates of survival.

A mechanically testable tissue was grown in vitro from rabbit chondrocytes that were initially plated at high density (approximately 80,000 cells/cm2). The DNA, collagen, and proteoglycan content, as well as the tissue thickness, tensile stiffness, and synthesis rates, were measured at 4, 6, and 8 weeks. The biochemical properties were similar to those for immature cartilage, with predominantly type-II collagen produced; this indicated that the cells retained their chondrocytic phenotype. The tissue formed a coherent mechanical layer with testable tensile stiffness as early as 4 weeks. The tensile elastic modulus reached 1.3 MPa at 8 weeks, which is in the range of values for native cartilage from the midzone. Collagen density was approximately 24 mg/ml at 8 weeks, which is about one-half the value for native cartilage, and the collagen fibril diameters were smaller. Chondrocytes in culture responded to culture conditions and were stimulated by cytokine <em>interleukin</em>-1beta. When culture conditions were varied to RPMI nutrient medium with lower fetal bovine serum and higher ascorbic acid concentrations, the thickness decreased and the modulus increased significantly. <em>Interleukin</em>-1beta, added to the 8-week culture for 2 weeks, caused a decrease of 60% in thickness, a decrease of 81% in proteoglycan content, and a decrease of <em>31</em>% in collagen content; this is similar to the response of cartilage explants to <em>interleukin</em>-1beta. This cartilage analog may be useful as a model system to study structure-function relationships in cartilage or as cartilage-replacement tissue.

OBJECTIVE

Brucine (BRU), a natural plant alkaloid is reported to possess cytotoxic and antiproliferative activities. In this study we aimed to investigate its in vitro and in vivo antitumor and antiangiogenic effects.

METHODS

Cell proliferation and viability was assessed using microculture tetrazolium tests (MTT). As predictive markers we determined intracellular levels of vascular endothelial growth factor (VEGF), <em>Interleukin</em>-12 (IL-12), tumor necrosis factor (TNF-α), caspase-3, -8 and -9 by ELISA and enzymatic activity assays. In addition, anti-VEGF neutralization effect was evaluated to assess whether it could result in augmented anticancer efficacy than the single agent. Antitumor activity was evaluated against Ehrlich ascites and solid tumor models. 15×10(6) EAC cells were implanted intraperitoneally (i.p., ascites tumor) and subcutaneous (s.c., solid tumor) in Swiss albino mice. Mice with established tumors received brucine i.p. at 12.5, 25, and 50mg/kg for 14days in ascites tumor and 50mg/kg in solid tumor for 30days. Tumor volume, cell viability, angiogenic, anti-angiogenic, anti-inflammatory factors and antioxidant parameters were determined. Immunohistochemistry analysis for VEGF and CD-<em>31</em> was also performed.

RESULTS

BRU produced time and dose-dependent inhibition of MCF-7 in vitro and EAC tumors in vivo. The anti-angiogenic effects were accompanied with decreased VEGF and TNF-α and increased IL-12 expression. BRU reduced peritoneal angiogenesis and microvessel density in vivo.

CONCLUSIONS

Our findings suggest that BRU possesses antitumor and anti-angiogenic activities in vitro and in vivo. The above results showed that BRU can be used as a potential anticancer agent as an antimetastatic and anti-angiogenic agent.

In <em>31</em> patients with carcinoma of the breast the phenotype and activation status of tumour infiltrating lymphocytes (TILs) was analysed by flow cytometry. The predominant cells, in all patients, were T lymphocytes and in the majority of cases CD8+ (cytotoxic/suppressor) T lymphocytes were present in greater numbers than CD4+ (helper) T lymphocytes. There was no relationship between the degree of lymphocytic infiltration and either tumour stage or grade but there appeared to be an inverse correlation with the levels of oestrogen receptor (ER) in the tumour (P less than 0.01). Both populations of T cells had significantly higher numbers of cells carrying HLA DR (class II major histocompatibility antigen) than the equivalent populations in peripheral blood from the same patient group (P less than 0.001). The transferrin receptor was found on similar numbers of CD8+ T cells in peripheral blood and among the tumour infiltrating lymphocytes while more of the CD4+ T cells infiltrating the tumour were found to carry this receptor (P = 0.034). The Tac (CD 25) antigen was also on similar numbers of CD8+ T cells from both peripheral blood and the tumour but was on fewer of the CD4+ T cells in the tumour with respect to peripheral blood (P = 0.029). In both TILs and blood lymphocytes, the Tac antigen was consistently present on greater numbers of CD4+ T lymphocytes than on the CD8+ T lymphocytes (P less than 0.001) and as this is a component of the <em>interleukin</em> 2 (IL-2) receptor this may be of relevance to the use of IL-2 in TIL cancer therapy.

Matrix metalloproteinase-9 (MMP-9) activity is implicated in pathogenesis of central nervous system tuberculosis (CNS-TB). IFNgamma, a key cytokine in TB, usually inhibits MMP-9 secretion. Addition of IFNgamma to conditioned media from M. tb-infected monocytes (CoMTB) resulted in a 7-fold increase in MMP-9 activity detected by gelatin zymography (P<0.01). In contrast, tissue inhibitor of metalloproteinase (TIMP)-1 and -2 secretion, measured by ELISA, was suppressed. Dexamethasone abolished the synergistic increase in MMP-9 activity. <em>Interleukin</em> (IL)-1beta in CoMTB is a critical mediator of synergy with IFNgamma, and IL-1beta alone synergizes with IFNgamma to increase MMP-9 secretion from 51 +/- <em>31</em> to 762 +/- 136 U. IL-1beta activity is dependent on p38 mitogen-activated protein (MAPK) kinase, which was found to be phosphorylated in tissue specimens from patients with CNS-TB. Extracellular signal regulated kinase (Erk) and p38 MAPK activation did not affect IFNgamma signaling pathways. Inhibition of janus-activated kinase (JAK)-2 by 50 microM AG540 decreased MMP-9 secretion to 124 +/- 11.1 from 651 +/- 229 U of activity (P<0.01). However, signal transducer and activator of transcription (STAT)-3 but not STAT-1 phosphorylation was synergistically up-regulated by IFNgamma and CoMTB. In summary, synergy between IL-1beta and STAT-3 dependent IFNgamma signaling is key in control of up-regulation of MMP-9 activity in CNS-TB and may be a significant mechanism of brain tissue destruction.

BACKGROUND

Soluble interleukin-2 receptor (sIL2r), a marker of T cell activation, is elevated in inflammatory processes, such as rheumatoid arthritis, hepatitis and neoplasm. We explored a potential association between plasma sIL2r levels and progression of coronary artery calcification (CAC), a marker for subclinical atherosclerosis, in a prospectively followed cohort of type 1 diabetic and non-diabetic subjects, aged 20-59 years, with no history of coronary artery disease.

METHODS

CAC progression was assessed by electron beam tomography over 2.6 years (range 1.6-3.2). Plasma sIL2r levels were measured in a nested case-control substudy of 98 subjects (67 diabetic, 31 non-diabetic) with and 173 subjects (84 diabetic, 89 non-diabetic) without significant CAC progression. Log-transformed sIL2r levels were analyzed by conditional logistic regression to compare subjects with and without significant CAC progression.

RESULTS

SIL2r was a significant predictor for CAC progression after adjusting for presence of baseline CAC, age, gender, diabetes status, baseline calcium volume score and adiponectin (OR 1.99, 95% CI 1.09-3.61, p = 0.02 for a doubling of sIL2r level). Addition of BMI, LDL, HDL, hypertension, smoking status, HbA1c, CRP, fibrinogen, homocysteine and PAI-1 to regression models weakened but did not remove sIL2r as a predictor of CAC progression. There was no indication that this effect was different by diabetes status (p = 0.6 for diabetes-sIL2r interaction).

CONCLUSIONS

Elevated plasma sIL2r is associated with CAC progression independent of traditional coronary artery disease risk factors in type 1 diabetic and non-diabetic young adults. SIL2r should be considered as a novel marker of inflammation leading to coronary artery disease.

Kawasaki disease (KD) is a type of systemic vasculitis syndrome related to immune dysfunction. Previous studies have implicated that dysfunctional regulatory T cells (Treg ) may be associated with the immune dysfunction in KD. In the absence of microRNAs (miRNAs), forkhead box protein 3 (FoxP3)(+) Treg develop but fail to maintain immune homeostasis. This study was designed to investigate the effects of miR-155, miR-21 and miR-<em>31</em> on Treg in children with KD. The proportions of CD4(+) CD25(+) FoxP3(+) Treg and the mean fluorescence intensity (MFI) of phosphorylated-signal transducer and activator of transcription (pSTAT)-5 and pSTAT-3 protein in CD4(+) CD25(+) Treg were analysed by flow cytometry. The concentration of <em>interleukin</em> (IL)-6 in plasma was measured by cytometric bead array. Real-time polymerase chain reaction was performed to detect the levels of microRNAs and associated factors in CD4(+) CD25(+) Treg . The proportion of Treg and the mRNA levels of the associated factors [FoxP3, glucocorticoid-induced tumour necrosis factor-receptor (GITR), cytotoxic T lymphocyte antigen (CTLA)-4)] were significantly lower in KD patients (P < 0·05). MiR-155 and miR-21 levels were significantly down-regulated and miR-<em>31</em> expression was higher in KD patients (P < 0·05). Plasma <em>interleukin</em> (IL)-6 concentrations, pSTAT-3 protein levels and suppressors of cytokine signalling (SOCS)-1 mRNA expression were remarkably elevated in acute KD (P < 0·05), while pSTAT-5 protein levels were remarkably decreased in acute KD (P < 0·05). These findings were reversed after intravenous immunoglobulin treatment (P < 0·05). Our results demonstrate that FoxP3 mRNA levels were primarily affected by the miR-155/SOCS1 and the miR-<em>31</em> signalling pathways. These results suggest that the decrease in FoxP3(+) Treg might be associated with decreased expression of miR-155, leading to aberrant SOCS1/STAT-5 signalling and overexpression of miR-<em>31</em> in patients with acute KD.

<em>Interleukin</em>-<em>31</em> receptor A (IL-<em>31</em>RA) is a newly identified type I cytokine receptor, that is related to gp130, the common receptor of the <em>interleukin</em> (IL) -6 family cytokines. Recent studies have shown that IL-<em>31</em>RA forms a functional receptor complex for IL-<em>31</em> together with the beta subunit of oncostatin M receptor (OSMRbeta). However, little is known about the target cells of IL-<em>31</em> because it remains unclear which types of cells express IL-<em>31</em>RA. In our previous reports, we demonstrated that OSMRbeta is expressed in a subset of small-sized nociceptive neurons of adult dorsal root ganglia (DRGs). In the present study, we investigated the IL-<em>31</em>RA expression in the adult and developing DRGs. From a northern blot analysis and in situ hybridization histochemistry, IL-<em>31</em>RA mRNA was found to be expressed in the adult DRGs. According to reverse-transcriptase polymerase chain reaction, IL-<em>31</em>RA mRNA was detected in the DRGs and trigeminal ganglia, while no expression of IL-<em>31</em>RA mRNA was observed in the CNS. Double immunofluorescence staining revealed IL-<em>31</em>RA to be expressed in a subset of small-sized neurons, all of which colocalized with OSMRbeta. In addition, the expression of IL-<em>31</em> RA was detected in afferent fibers in the spinal cord and the dermis of the skin. We also found that the developmental expression pattern of IL-<em>31</em>RA was different from that of OSMRbeta; IL<em>31</em>RA-positive neurons in DRGs first appeared at postnatal day (PN) 10 and reached the adult level at PN14, whereas OSMRbeta-positive neurons were observed at PN0 for the first time. We previously demonstrated OSMRbeta-expressing neurons to decrease, however, they were not found to disappear in oncostatin M (OSM) -deficient mice. These findings suggest that IL-<em>31</em> and OSM may thus have redundant functions in the development of OSMRbeta-expressing neurons.

OBJECTIVE

To evaluate the safety and efficacy of the platelet-activating factor receptor antagonist BB-882 in the treatment of patients with sepsis.

METHODS

Double-blind, placebo-controlled, randomized, multi-centered study.

METHODS

Thirty-four European intensive care units.

METHODS

One hundred fifty-two patients with clinical suspicion of infection and a mean APACHE II score between 15 and 35 in the 24 hrs before entry into the trial.

METHODS

Patients received either a loading dose of 4 mg of BB-882 on the first day, followed by an intravenous infusion of 96 mg/24 hrs for up to 120 hrs, or placebo.

METHODS

Hemodynamic, respiratory and oxygen transport variables, blood lactate concentrations, interleukin-6, interleukin-8, tumor necrosis factor (TNF)-alpha, soluble TNF receptor concentrations, organ failure score, 28-day mortality rate, Acute Physiology And Chronic Health Evaluation (APACHE) II score within 24 hrs of entry.

RESULTS

Sixty-nine patients (42 male, 27 female) received placebo and 83 (59 male, 24 female) received BB-882. Patients ranged in age from 16 to 89 yrs (mean, 60 yrs). No important differences existed between the two groups in terms of gender distribution, age, or initial APACHE II score. Sepsis was identified as Gram-positive in 49 patients, Gram-negative in 40, mixed in 37, and unknown in 26. No important differences were shown in hemodynamic, respiratory, or oxygen transport variables between groups during the study. Organ failure scores were similar in the two groups throughout the study. Cytokine concentrations were not significantly different in the two groups. Within 28 days of entering the study, 75 patients died, including 31 (45%) in the placebo group and 44 (53%) in the treatment group, p = .32. The median time to death in the placebo group was 6.0 days, and in the treatment group, it was 4.5 days (p = .30).

CONCLUSIONS

Treatment of sepsis with the platelet-activating factor antagonist BB-882 offers no advantage over placebo on survival, hemodynamic status, respiratory function, or organ failure scores.

OBJECTIVE

Moderate alcohol consumption exerts a cardioprotective effect, but no studies have evaluated the alcohol-independent cardiovascular effects of the non-alcoholic components of beer. We aimed to evaluate the effects of ethanol and the phenolic compounds of beer on classical and novel cardiovascular risk factors.

RESULTS

Thirty-three high risk male volunteers were included in a randomized, crossover feeding trial. After a washout period, all subjects received beer (30 g alcohol/d, 660 mL), the equivalent amount of polyphenols as non-alcoholic beer (990 mL), and gin (30 g alcohol/d, 100 mL) for 4 weeks. All outcomes were evaluated before and after each intervention period. Moderate alcohol consumption increased serum HDL-cholesterol (∼5%), ApoA-I (∼6%), ApoA-II (∼7%) and adiponectin (∼7%), and decreased serum fibrinogen (∼8%), and <em>interleukin</em> (IL)-5 (∼14%) concentrations, whereas the non-alcoholic fraction of beer (mainly polyphenols) increased the receptor antagonist of IL-1 (∼24%), and decreased lymphocyte expression of lymphocyte function-associated antigen-1 (∼11%), lymphocyte and monocyte expression of Sialil-Lewis X (∼16%) and monocyte expression of CCR2 (∼<em>31</em>%), and tumor necrosis factor (TNF)-β (∼14%) and IL-15 (∼22%) plasma concentrations. No changes were observed in glucose metabolism parameters or in body weight and adiposity parameters.

CONCLUSIONS

The phenolic content of beer reduces leukocyte adhesion molecules and inflammatory biomarkers, whereas alcohol mainly improves the lipid profile and reduces some plasma inflammatory biomarkers related to atherosclerosis.

OBJECTIVE

To investigate whether a range of cytokines were detectable in the seminal plasma and urine of men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and nonspecific urethritis (NSU), and whether cytokine levels correlated with symptom severity in CP/CPPS.

METHODS

In all, 87 men participated, 33 with CP/CPPS, <em>31</em> with NSU, and 23 controls. <em>Interleukin</em> (IL)-1beta, IL-2, IL-6, IL-8 and IL-10 were measured in seminal plasma and first pass urine, and the results were correlated with scores for pain, urinary symptoms and quality-of-life impact using a validated symptom index, the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI).

RESULTS

Seminal plasma levels of IL-8 were higher in men with CP/CPPS and NSU than in controls (P < 0.001), and the levels correlated with NIH-CPSI symptom scores in men with CP/CPPS. There were no significant differences in urinary IL-8 levels in the three groups, and no significant differences in levels of the other cytokines in either semen or urine.

CONCLUSIONS

Semen IL-8 levels correlate with subjective symptoms in men with CP/CPPS. IL-8 might contribute to the pathophysiology of CP/CPPS and NSU, and elevated levels might be a useful marker of the condition.

BACKGROUND

Uremic pruritus (UP) is still a common tormenting symptom among patients on hemodialysis (HD). The pathogenesis of UP is complex and not fully clarified. Some preliminary studies indicate that UP is a systemic inflammatory disease with a deranged balance of T helper (TH) cell differentiation toward TH1 predominance. The aim of this study was to further elucidate the potential contribution of TH1 cytokines to the pathogenesis of UP.

METHODS

In this study, 112 HD patients were screened for UP. After meeting the required criteria, <em>31</em> HD patients with UP were included in the study as case group and 30 age- and sex-matched HD patients without UP were enrolled as controls. The serum levels of <em>interleukin</em> (IL)-2 and interferon-γ (as TH1 cytokines), IL-4 (as a TH-2 cytokine), high-sensitive C-reactive protein (as an inflammatory marker), parathyroid hormone, calcium, phosphate, albumin and ferritin were measured in all patients. Moreover, blood variables including hemoglobin and mean corpuscular volume were also determined. The correlations of measured factors with UP severity were determined as well.

RESULTS

Except for the serum levels of IL-2, which were significantly higher in HD patients with itch versus those without it [0.544 ± 0.126 (U/mL) versus 0.<em>31</em>8 ± 0.145 (U/mL); P < 0.0001], no statistically significant difference was observed in the levels of each of the above-mentioned factors between the two groups. Additionally, no correlation was detected between the levels of measured factors and UP severity.

CONCLUSIONS

The results of our study, for the first time, point to the potential important role of IL-2 in UP and further support the notion of TH1 overactivity in its pathogenesis. Our study paves the way for further studies focusing on the contribution of IL-2 to the UP, such as the experimental use of anti-IL-2 receptor antibodies.

Acute kidney injury (AKI) frequently occurs in critically ill patients and often precipitates use of renal replacement therapy (RRT). However, the ideal circumstances for whether and when to start RRT remain unclear. We performed evidence synthesis of the available literature to evaluate the value of biomarkers to predict receipt of RRT for AKI.

We conducted a PRISMA-guided systematic review and meta-analysis including all trials evaluating biomarker performance for prediction of RRT in AKI. A systematic search was applied in MEDLINE, Embase, and CENTRAL databases from inception to September 2017. All studies reporting an area under the curve (AUC) for a biomarker to predict initiation of RRT were included.

Sixty-three studies comprising 15,928 critically ill patients (median per study 122.5 [<em>31</em>-1439]) met eligibility. Forty-one studies evaluating 13 different biomarkers were included. Of these biomarkers, neutrophil gelatinase-associated lipocalin (NGAL) had the largest body of evidence. The pooled AUCs for urine and blood NGAL were 0.720 (95% CI 0.638-0.803) and 0.755 (0.706-0.803), respectively. Blood creatinine and cystatin C had pooled AUCs of 0.764 (0.732-0.796) and 0.768 (0.729-0.807), respectively. For urine biomarkers, <em>interleukin</em>-18, cystatin C, and the product of tissue inhibitor of metalloproteinase-2 and insulin growth factor binding protein-7 showed pooled AUCs of 0.668 (0.606-0.729), 0.722 (0.575-0.868), and 0.857 (0.789-0.925), respectively.

Though several biomarkers showed promise and reasonable prediction of RRT use for critically ill patients with AKI, the strength of evidence currently precludes their routine use to guide decision-making on when to initiate RRT.

OBJECTIVE

Cryopyrin-associated periodic syndromes (CAPS) represent a spectrum of CIAS1 gene-mediated autoinflammatory diseases characterized by recurrent systemic inflammation. The clinical spectrum of CAPS varies from mild to severe and includes the syndromes historically described as familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). This article presents the largest cohort of patients with CAPS. The objective is to describe the pathogenesis, otolaryngologic, and audiologic manifestations of CAPS.

METHODS

Prospective (2003-2009).

METHODS

National Institutes of Health.

METHODS

Fifty-seven patients with a diagnosis of CAPS were identified (<em>31</em> NOMID, 11 NOMID/MWS, 9 MWS, and 6 FCAS). Comprehensive data regarding clinical manifestations, audiologic phenotype, and fluid attenuation inversion recovery MRI (FLAIR-MRI) of the brain and inner ear were obtained.

RESULTS

Complete audiologic data obtained on 70% of ears revealed conductive hearing loss in 4 (11%) NOMID ears and mixed hearing loss in 5 (13%) NOMID and 2 (14%) NOMID/MWS ears. Sensorineural hearing loss (SNHL), worse in higher frequencies, was the most common type of hearing loss and was present in 23 (61%) NOMID, 10 (71%) NOMID/MWS, and 4 (33%) MWS ears. All of the patients with FCAS had normal hearing except 2, who had SNHL from 4 to 8 kHz. On FLAIR-MRI sequence, cochlear enhancement was noted in 26 of 29 (90%) NOMID, 6 of 11 (55%) NOMID/MWS, 3 of 9 (33%) MWS, and 1 of 6 (17%) FCAS patients and was significantly associated with the presence of hearing loss. Maxillary sinus hypoplasia and mucosal thickening were found in 39% and 86% of the cohort, respectively.

CONCLUSIONS

CIAS1 pathway–mediated CAPS is associated with unregulated autoinflammation mediated by interleukin-1 in the cochlea and hearing loss. Timely diagnosis is crucial to initiate early treatment with interleukin-1 receptor antagonists.

BACKGROUND

The most intriguing function attributed to <em>interleukin</em>-<em>31</em> (IL-<em>31</em>) is its ability to induce pruritus in pathologic conditions, such as atopic dermatitis (AD). As of today, this feature of IL-<em>31</em> was tested in vivo only in animal models.

METHODS

Ten patients with AD and 10 healthy controls were challenged with IL-<em>31</em> and NaCl (negative control) by skin prick testing. Twenty additional healthy controls were subjected to skin prick testing with histamine. Itch and local inflammatory responses of the skin were assessed for up to 72 h.

RESULTS

All of the histamine-challenged subjects developed immediate pruritus (i.e. within the first 5 min). In contrast, only one IL-<em>31</em>- and two of the NaCl-challenged subjects reported immediate itch at the provocation site (short lasting, for 2-6 min). Nine subjects (five patients with AD) reported late itch responses to IL-<em>31</em> challenges with a mean delay of 143 min. No subject reported late itch responses to histamine or NaCl testing. There was no significant difference in IL-<em>31</em>-induced itch start time, duration and intensity between patients with AD and healthy volunteers.

CONCLUSIONS

IL-<em>31</em> does not induce immediate itch responses in humans. The late onset of IL-<em>31</em>-induced itch supports the notion that IL-<em>31</em> exerts its pruritic effect indirectly via keratinocytes and secondary mediators, rather than through its receptors on cutaneous nerves.

Osteoprotegerin (OPG) is a decoy receptor for receptor activator of NF-kappaB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). While RANKL is essential for osteoclastogenesis and facilitates breast cancer migration into bone, TRAIL promotes breast cancer apoptosis. We analyzed the expression of OPG and TRAIL and its modulation in estrogen receptor-positive MCF-7 cells and receptor-negative MDA-MB-2<em>31</em> cells. In both cells, OPG mRNA levels and protein secretion were dose- and time-dependently enhanced by <em>interleukin</em> (IL)-1beta and suppressed by dexamethasone. In contrast to MCF-7 cells, MDA-MB-2<em>31</em> abundantly expressed TRAIL mRNA, which was enhanced by IL-1beta and inhibited by dexamethasone. TRAIL activated pro-apoptotic caspase-3, -7, and poly-ADP-ribose polymerase and decreased cell numbers of MDA-MB-2<em>31</em>, but had no effect on MCF-7 cells. Gene silencing siRNA directed against OPG resulted in a <em>31</em>% higher apoptotic rate compared to non-target siRNA-treated MDA-MB-2<em>31</em> cells. Furthermore, TRAIL induced significantly less apoptosis in cells cultured in conditioned media (containing OPG) compared to cells exposed to TRAIL in fresh medium lacking OPG (P < 0.01) and these protective effects were reversed by blocking OPG with its specific ligand RANKL (P < 0.05). The association between cancer cell survival and OPG production by MDA-MB-2<em>31</em> cells was further supported by the finding, that modulation of OPG secretion using IL-1beta or dexamethasone prior to TRAIL exposure resulted in decreased and increased rate of apoptosis, respectively (P < 0.05). Thus, OPG secretion by breast cancer cells is modulated by cytokines and dexamethasone, and may represent a critical resistance mechanism that protects against TRAIL-induced apoptosis.

OBJECTIVE

In this study, the effects of vibration therapy (VT) on delayed-onset muscle soreness (DOMS) and associated inflammatory markers after downhill running were determined.

METHODS

29 male recreational runners (33 (8) years; V(O2)peak 57 (6) ml kg(-1) min(-1)) completed a 40-min downhill run and were randomly allocated to a VT group or Control group. For 5 days post-run, the VT group underwent once-daily sessions of VT on the upper and lower legs. DOMS was assessed pre-run and for 5 days post-run by visual analogue scale. Immune cell subsets and plasma inflammatory markers were assessed pre-run, post-run, 24 and 120 h post-run by full differential cell count, and by ELISA and enzyme immunoassay, respectively. Data were analysed as per cent change from pre-run (ANOVA) and the magnitude of the treatment effect (Cohen's effect size statistics).

RESULTS

VT significantly reduced calf pain 96 h post-run (-50% (40%), 90% confidence limits) and gluteal pain 96 h (-50% (40%)) and 120 h post-run (-30% (30%)); decreased <em>interleukin</em> 6 (IL6) 24 h (-46% (<em>31</em>%)) and 120 h post-run (-65% (30%)); substantially decreased histamine 24 h (-40% (50%)) and 120 h post-run (-37% (48%)); substantially increased neutrophils (8.6% (8.1%)) and significantly decreased lymphocytes (-17% (12%)) 24 h post-run. There were no clear substantial effects of VT on other leukocyte subsets and inflammatory markers.

CONCLUSIONS

VT reduces muscle soreness and IL6. It may stimulate lymphocyte and neutrophil responses and may be a useful modality in treating muscle inflammation.

Hepcidin regulation by competing stimuli such as infection and iron deficiency has not been studied in infants and it's yet unknown whether hepcidin regulatory pathways are fully functional in infants. In this cross-sectional study including 339 Kenyan infants aged 6.0±1.1 months (mean±SD), we assessed serum hepcidin-25, biomarkers of iron status and inflammation, and fecal calprotectin. Prevalence of inflammation, anemia, and iron deficiency was <em>31</em>%, 71%, 26%, respectively. Geometric mean (±SD) serum hepcidin was 6.0 (±3.4) ng/mL, and was significantly lower in males than females. Inflammation (C-reactive protein and <em>interleukin</em>-6) and iron status (serum ferritin, zinc protoporphyrin and soluble transferrin receptor) were significant predictors of serum hepcidin, explaining nearly 60% of its variance. There were small, but significant differences in serum hepcidin comparing iron deficient anemic (IDA) infants without inflammation to iron-deficient anemic infants with inflammation (1.2 (±4.9) vs. 3.4 (±4.9) ng/mL; P<0.001). Fecal calprotectin correlated with blood/mucus in the stool but not with hepcidin. Similarly, the gut-linked cytokines IL-12 and IL-17 did not correlate with hepcidin. We conclude that hepcidin regulatory pathways are already functional in infancy, but serum hepcidin alone may not clearly discriminate between iron-deficient anemic infants with and without infection. We propose gender-specific reference values for serum hepcidin in iron-replete infants without inflammation.

OBJECTIVE

Compare the expression and regulation of nuclear receptors (NRs) in osteoarthritic and normal human articular cartilage.

METHODS

The transcriptional levels of 48 NRs and additional related proteins were measured in mRNA from human articular cartilage from subjects with osteoarthritis (OA) and compared to samples from subjects without OA, using microarrays, individual quantitative reverse transcriptase polymerase chain reaction assays, and a custom human NR TaqMan Low Density Array (TLDA). The functional effect of liver X receptor (LXR) activity in cartilage was studied by measuring proteoglycan (PG) synthesis and degradation in articular cartilage explant cultures following treatment with the synthetic LXR agonist T0901<em>31</em>7.

RESULTS

Thirty-one of 48 NRs analyzed by TLDA were found to be measurably expressed in human articular cartilage; 23 of these <em>31</em> NRs showed significantly altered expression in OA vs unaffected cartilage. Among these, LXRalpha and LXRbeta, and their heterodimeric partners retinoid X receptor (RXR)alpha and RXRbeta were all expressed at significantly lower levels in OA cartilage, as were LXR target genes ABCG1 and apolipoproteins D and E. Addition of LXR agonist to human OA articular chondrocytes and to cartilage explant cultures resulted in activation of LXR-mediated transcription and significant reduction of both basal and <em>interleukin</em> (IL)-1-mediated PG degradation.

CONCLUSIONS

Articular cartilage expresses a substantial number of NRs, and a large proportion of the expressed NRs are dysregulated in OA. In particular, LXR signaling in OA articular cartilage is impaired, and stimulation of LXR transcriptional activity can counteract the catabolic effects of IL-1. We conclude that LXR agonism may be a possible therapeutic option for OA.

OBJECTIVE

Cytokines are immunomodulatory proteins important in cell signaling. Complex interactions of innate and adaptive immune cells, as well as structural cells and their cytokines, play crucial roles in regulating allergic airway inflammation. Here, we summarize current knowledge about the potential roles of known and newly identified helper T cells and epithelial cell-derived cytokines [interleukin (IL)-9, IL-17, IL-22, IL-25, and IL-33] in allergic rhinitis and asthma.

RESULTS

Although T-helper (Th)2 cells were considered to be the main orchestrators of allergic airway inflammation, recent studies have revealed the potential interaction of other helper T cells and their cytokines in this process. Th17 cells may have a role in allergic rhinitis and asthma, and chronic rhinosinusitis with nasal polyps. An IL-9-producing subset called Th9 cells, Th22 cells which primarily secrete IL-22, IL-13, tumor necrosis factor-α, Th25 cells via producing IL-25 and epithelial cell-derived thymic stromal lymphopoietin, IL-33, IL-31, and IL-25 are believed to be important for the initiation of allergic reactions and inducing airway inflammation.

CONCLUSIONS

A new paradigm of an interplay of cytokines is important in allergic rhinitis and asthma in orchestrating the allergic inflammatory response. Potential therapeutic applications emerging from the roles of these cytokines are promising, but need further research.