Disease-Association Analysis of an Inflammation-Related Feedback Loop

SummaryThe IL-6-triggered positive feedback loop for NFκB signaling (or the IL-6 amplifier/Inflammation amplifier) was originally discovered as a synergistic-activation signal that follows IL-17/IL-6 stimulation in nonimmune cells. Subsequent results from animal models have shown that the amplifier is activated by stimulation of NFκB and STAT3 and induces chemokines and inflammation via an NFκB loop. However, its role in human diseases is unclear. Here, we combined two genome-wide mouse screens with SNP-based disease association studies, revealing 1,700 genes related to the IL-6 amplifier, 202 of which showed 492 indications of association with ailments beyond autoimmune diseases. We followed up on ErbB1 from our list. Blocking ErbB1 signaling suppressed the IL-6 amplifier, whereas the expression of epiregulin, an ErbB1 ligand, was higher in patients with inflammatory diseases. These results indicate that the IL-6 amplifier is indeed associated with human diseases and disorders and that the identified genes may make for potential therapeutic targets

Short-Term Temporal Metabolic Behavior in Halophilic Cyanobacterium Synechococcus sp. Strain PCC 7002 after Salt Shock

In response to salt stress, cyanobacteria increases the gene expression of Na+/H+ antiporter and K+ uptake system proteins and subsequently accumulate compatible solutes. However, alterations in the concentrations of metabolic intermediates functionally related to the early stage of the salt stress response have not been investigated. The halophilic cyanobacterium Synechococcus sp. PCC 7002 was subjected to salt shock with 0.5 and 1 M NaCl, then we performed metabolomics analysis by capillary electrophoresis/mass spectrometry (CE/MS) and gas chromatography/mass spectrometry (GC/MS) after cultivation for 1, 3, 10, and 24 h. Gene expression profiling using a microarray after 1 h of salt shock was also conducted. We observed suppression of the Calvin cycle and activation of glycolysis at both NaCl concentrations. However, there were several differences in the metabolic changes after salt shock following exposure to 0.5 M and 1 M NaCl: (i): the main compatible solute, glucosylglycerol, accumulated quickly at 0.5 M NaCl after 1 h but increased gradually for 10 h at 1 M NaCl; (ii) the oxidative pentose phosphate pathway and the tricarboxylic acid cycle were activated at 0.5 M NaCl; and (iii) the multi-functional compound spermidine greatly accumulated at 1 M NaCl. Our results show that Synechococcus sp. PCC 7002 acclimated to different levels of salt through a salt stress response involving the activation of different metabolic pathways

Composite assessment of power Doppler ultrasonography and MRI in rheumatoid arthritis: a pilot study of predictive value in radiographic progression after one year

Objective: Power Doppler ultrasonography (PDUS) and MRI are independently useful to predict structural damage in patients with rheumatoid arthritis (RA). We hypothesize that there is a complementary relationship between these modalities. The aim of this study is, therefore, to investigate the usefulness of the predictive value of composite assessment of PDUS and contrast-enhanced MRI in radiographic outcomes in patients with RA. Methods: 20 patients (17 females and 3 males) with RA on disease-modifying antirheumatic drugs underwent PDUS and MRI of both hands at baseline. Radiography of the bilateral hands was performed at baseline and at 1 year, Articular synovitis on PDUS was evaluated according to quantitative measurement. Synovitis, bone marrow edema and bone erosion were scored according to the RA MRI scoring method. The changes of joint space narrowing and bone erosion on radiograph were assessed by the Sharp/van der Heijde method. We applied t-statistics to combine the assessment of quantitative PDUS with semiquantitative MRI. Results: Structural damage progression for radiography was not correlated with any evaluations for MRI, while it showed significant correlation with synovitis on PDUS (r(s) = 0.597, p = 0.005). The composite assessment of both modalities (synovitis for PDUS and bone marrow edema for MRI) was correlated with structural damage progression on radiograph (r(s) = 0.792, p < 0.0001). Conclusion: Composite assessment of PDUS and MRI may have a stronger predictive value in radiographic progression than PDUS or MRI alone in RA. Advances In knowledge: Composite assessment of PDUS and MRI may be an effective predictor of structural damage in RA

Power Doppler signal calibration in the finger joint between two models of ultrasound machine: a pilot study using a phantom and joints in patients with rheumatoid arthritis

Background: Despite the advantages of ultrasound (US) in the management of rheumatoid arthritis (RA) patients, power Doppler (PD) US may be highly dependent on the type of US machine used. Purpose: To present a method to calibrate the PD signal of two models of US machines by use of a flow phantom and finger joints of patients with RA. Material and Methods: For the phantom study, the PD signal count was measured in the flow phantom perfusing blood mimicking fluid at various injection rates and pulse repetition frequencies (PRFs). The quantitative PD index was calculated with ImageJ. For the clinical study, the second and third metacarpophalangeal joints of five consecutive patients with RA were examined. The quantitative PD index was measured at various PRFs by use of two models of machine (the same models as the phantom study). Results: For the phantom and clinical studies, negative correlations were found between the PRF and the quantitative PD index when the flow velocity was constant and positive correlations between flow velocity and the quantitative PD index at constant PRF. There was a significant difference in the depiction performance of synovial blood flow between the two models, which can be calibrated by adjusting the PRF values derived from the phantom study in each model. Conclusion: Signal calibration of pannus vascularity between US machines may be possible by adjusting the PRF value according to flow phantom data. Different US machines can thus provide equivalent examination results concerning the pannus vascularity

Safety and effectiveness of monthly intravenous ibandronate injections in a prospective, postmarketing, and observational study in Japanese patients with osteoporosis

Objectives: This postmarketing, observational study evaluated the safety and effectiveness of monthly intravenous (IV) ibandronate in Japanese patients with osteoporosis. Methods: Eligible patients received monthly IV ibandronate 1 mg for 12 months. Adverse drug reactions (ADRs) were evaluated. Changes in bone mineral density (BMD) and bone turnover markers (BTMs) were assessed using matched t-test analysis. Cumulative fracture rates were analyzed by Kaplan-Meier methodology. Results: In total, 1062 patients were enrolled, of whom 1025 (n = 887 women, n = 138 men) were treated. Mean patient age was 77 years. Seventy-five ADRs were reported in 54 patients (5.26%). Four patients (0.39%) experienced serious ADRs, including one case of osteonecrosis of the jaw. Acute-phase reactions occurred in 21 patients (2.04%), and half of them arose after the first ibandronate injection. No new safety concerns were identified. Significant increases in BMD at 12 months relative to baseline were observed at the lumbar spine (4.84%, n = 187; 95% confidence interval [CI], 3.47%–6.21%), femoral neck (2.73%, n = 166; 95% CI, 1.46%–4.01%), and total hip (1.93%, n = 133; 95% CI, 0.80%–3.07%). Significant reductions were observed in all BTMs at 12 months (n = 174 in tartrate-resistant acid phosphatase-5b, n = 101 in procollagen type 1 N-terminal propeptide at baseline). The cumulative incidence of nontraumatic, new vertebral and nonvertebral fractures was 3.16% (95% CI, 2.12%–4.70%). Analyses in women only showed similar results to the overall population. Conclusions: These findings confirm the favorable safety and consistent effectiveness of ibandronate, and indicate that monthly IV ibandronate would be beneficial in daily practice for the treatment of Japanese patients with osteoporosis. Keywords: Ibandronate, Intravenous, Japan, Osteoporosis, Prospective observational stud

Quantitative power Doppler signal assessment in the subchondral bone region of the metacarpophalangeal joint is an effective predictor of radiographic progression in the hand of rheumatoid arthritis: a pilot study

Ultrasonography is useful for assessment of synovitis in the hand of rheumatoid arthritis (RA) patients. The aim of this study was to investigate the predictive value of the quantitative power Doppler (PD) signal assessment in the subchondral bone region of the metacarpophalangeal (MCP) joint in patients with RA showing radiographic progression of the hand by comparing with those of previously reported scoring systems. Twenty-two patients (20 women) with RA who underwent power Doppler ultrasonography (PDUS) of the bilateral one to five MCP joints at baseline were included in the study. Radiography of both hands was performed at baseline and at 1year. PDUS of the synovial space was evaluated according to semi-quantitative scoring (0-3) and quantitative measurement (0-100%). The PD signal in the subchondral bone region was qualitatively (0, 1) and quantitatively (mm(2)) assessed. The performance of PDUS assessment was compared using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve and the risk ratio (RR). As a predictor for radiographic progression, the quantitative PD signal assessment in the subchondral bone region (AUC=0.842, p<0.01) was equivalent to quantitative vascularity (AUC=0.817, p<0.05) and semi-quantitative scoring (AUC=0.754, p<0.05). As for the RR of the PD signal in the subchondral bone region for radiographic progression, the quantitative PD signal assessment was 5.40 (p<0.01), whereas the qualitative PD signal assessment was 1.60 (p=0.204). Quantitative PD signal assessment in the subchondral bone region can predict radiographic progression in the hand of RA patients