Inhibition of Bruton's TK regulates macrophage NF-kappa B and NLRP3 inflammasome activation in metabolic inflammation

Background and Purpose: There are no medications currently available to treat metabolic inflammation. Bruton's tyrosine kinase (BTK) is highly expressed in monocytes and macrophages and regulates NF-\u3baB and NLRP3 inflammasome activity; both propagate metabolic inflammation in diet-induced obesity. Experimental Approach: Using an in vivo model of chronic inflammation, high-fat diet (HFD) feeding, in male C57BL/6J mice and in vitro assays in primary murine and human macrophages, we investigated if ibrutinib, an FDA approved BTK inhibitor, may represent a novel anti-inflammatory medication to treat metabolic inflammation. Key Results: HFD-feeding was associated with increased BTK expression and activation, which was significantly correlated with monocyte/macrophage accumulation in the liver, adipose tissue, and kidney. Ibrutinib treatment to HFD-fed mice inhibited the activation of BTK and reduced monocyte/macrophage recruitment to the liver, adipose tissue, and kidney. Ibrutinib treatment to HFD-fed mice decreased the activation of NF-\u3baB and the NLRP3 inflammasome. As a result, ibrutinib treated mice fed HFD had improved glycaemic control through restored signalling by the IRS-1/Akt/GSK-3\u3b2 pathway, protecting mice against the development of hepatosteatosis and proteinuria. We show that BTK regulates NF-\u3baB and the NLRP3 inflammasome specifically in primary murine and human macrophages, the in vivo cellular target of ibrutinib. Conclusion and Implications: We provide \u201cproof of concept\u201d evidence that BTK is a novel therapeutic target for the treatment of diet-induced metabolic inflammation and ibrutinib may be a candidate for drug repurposing as an anti-inflammatory agent for the treatment of metabolic inflammation in T2D and microvascular disease

Diagnosis / Intervention criteria in damaged slabs by severe corrosion of prestressed joists

This research defines diagnosis criteria in R/C one-way slabs with severe corrosion at the lower prestressed reinforcement of the joists and proposes specific actuation criteria and constructive recommendations to increase the safety. The corrosion of this reinforcement is the most common damage in building structures, and the use of aluminous cement in the precast joists can aggravate the corrosion. The usual cases of entire residential buildings with different degrees of damage and with a few or all joists affected in a slab have been simulated. ACI-318 is used as an acceptance criterion for existing structures in the simulations, and a ratio between the ultimate load and the service load is defined as valuation coefficient. By this way, the residual safety for a damaged structure is known. Results are in accordance with the extensive experience in real intervention cases, which often still have high safety reserves.Vercher Sanchis, JM.; Gil Benso, E.; Mas Tomas, MDLA.; Lerma Elvira, C. (2013). Diagnosis / Intervention criteria in damaged slabs by severe corrosion of prestressed joists. Journal of Performance of Constructed Facilities. (04014040). doi:10.1061/(ASCE)CF.1943-5509.0000515S0401404

Analysis of the residual safety level in R/C slabs with severe joist corrosion

An analysis until the failure on a series of one-way slabs with severe corrosion at the lower reinforcement of the R/C joists is presented. Different positions in the slab and number of damaged joists have been studied, obtaining the residual safety assessment in cases of slabs damaged by flexural failure mechanisms. Since the boundary conditions have proved decisive for obtaining the behavior, the damaged slab has been evaluated as part of the entire building, as precisely as possible, taking into account the different phases of the construction process and deterioration in time, and the complex behavior of concrete, steel and masonry. The results of the proposed methodology are consistent with the pathology of the observed cases. As a result of this study the authors propose practical recommendations to help in making decisions about the magnitude of the intervention, always necessary in this type of pathology.Vercher Sanchis, JM.; Gil Benso, E.; Mas Tomas, MDLA.; Cubel Arjona, FJ. (2014). Analysis of the residual safety level in R/C slabs with severe joist corrosion. Journal of Performance of Constructed Facilities. 1-14. doi:10.1061/(ASCE)CF.1943-5509.0000608S11

Factor structure of the Hospital Anxiety and Depression Scale in Japanese psychiatric outpatient and student populations

<p>Abstract</p> <p>Background</p> <p>The Hospital Anxiety and Depression Scale (HADS) is a common screening instrument excluding somatic symptoms of depression and anxiety, but previous studies have reported inconsistencies of its factor structure. The construct validity of the Japanese version of the HADS has yet to be reported. To examine the factor structure of the HADS in a Japanese population is needed.</p> <p>Methods</p> <p>Exploratory and confirmatory factor analyses were conducted in the combined data of 408 psychiatric outpatients and 1069 undergraduate students. The data pool was randomly split in half for a cross validation. An exploratory factor analysis was performed on one half of the data, and the fitness of the plausible model was examined in the other half of the data using a confirmatory factor analysis. Simultaneous multi-group analyses between the subgroups (outpatients vs. students, and men vs. women) were subsequently conducted.</p> <p>Results</p> <p>A two-factor model where items 6 and 7 had dual loadings was supported. These factors were interpreted as reflecting anxiety and depression. Item 10 showed low contributions to both of the factors. Simultaneous multi-group analyses indicated a factor pattern stability across the subgroups.</p> <p>Conclusion</p> <p>The Japanese version of HADS indicated good factorial validity in our samples. However, ambiguous wording of item 7 should be clarified in future revisions.</p

Bruton’s tyrosine kinase (BTK) regulates myeloid cell recruitment during acute inflammation

Background and Purpose Bruton's tyrosine kinase (BTK) is a non-receptor kinase best known for its role in B lymphocyte development that is critical for proliferation, and survival of leukemic cells in B cell malignancies. However, BTK is expressed in myeloid cells, particularly neutrophils, monocytes and macrophages where its inhibition has been reported to exhibit anti-inflammatory properties. Experimental Approach We explored the role of BTK on the migration of myeloid cells (neutrophils, monocytes and macrophages); in vitro using chemotaxis assays and in vivo using zymosan induced peritonitis as model systems. Key Results Using the zymosan induced peritonitis model of sterile inflammation we demonstrated that acute inhibition of BTK prior to zymosan challenge reduced phosphorylation of BTK in circulating neutrophils and monocytes. Moreover, we demonstrated that pharmacological inhibition of BTK with ibrutinib specifically inhibits neutrophil and Ly6Chi monocytes, but not Ly6Clo monocyte recruitment to the peritoneum. XID mice, which have a point mutation in the Btk gene had reduced neutrophil and monocyte recruitment to the peritoneum following zymosan challenge. To better understand the role of BTK in myeloid cell recruitment we investigated both chemotaxis and chemokine production in macrophages. Pharmacological or genetic inhibition of BTK signalling substantially reduced human monocyte and murine macrophage chemotaxis, to a range of clinically relevant chemoattractants (C5a and CCL2). We also demonstrated that inhibition of BTK in tissue resident macrophages significantly decreases chemokine secretion by reducing NF-kB activity and Akt signalling. Conclusion and Implications Our work has identified a new role of BTK in regulating myeloid cell recruitment via two mechanisms, 1) reducing monocyte/macrophages’ ability to undergo chemotaxis, and 2) reducing chemokine secretion, via reduced NF-kB and Akt activity in tissue resident macrophages

Inhibition of Bruton's tyrosine kinase regulates macrophage NF-κB and NLRP3 inflammasome activation in metabolic inflammation

Background and Purpose Currently there are limited medicines available for the treatment of metabolic inflammation in diseases such as obesity and type 2 diabetes (T2D). Although initially associated with B‐ells, Bruton's tyrosine kinase (BTK) is present in a wide variety of cells including monocytes and macrophages, and has been implicated in the regulation of the NF‐κB and NLRP3 inflammasome activity. Experimental Approach Using in vivo models of chronic inflammation [high‐fat‐diet (HFD) feeding] and in vitro assays in primary murine and human macrophages we investigated if ibrutinib, an FDA approved medicine that targets BTK, may represent a novel anti‐inflammatory drug for the use in treating metabolic inflammation. Key results HFD feeding was associated with increased BTK expression and activation, which was significantly correlated with monocyte/macrophage accumulation in the liver, adipose tissue and kidney. Treatment of mice fed HFD with ibrutinib inhibited the activation of BTK and reduced monocyte/macrophage recruitment to the liver, adipose tissue and kidney. Reduced inflammatory gene expression associated with decreased activation of NF‐κB and the NLRP3 inflammasome in vivo. As a result, ibrutinib treated mice fed HFD had improved glycaemic control through restored signalling by the IRS‐1/Akt/GSK‐3β pathway; protecting mice against the development of hepatosteatosis and proteinuria. We show that inhibition of BTK reduces activation of NF‐κB and the NLRP3 inflammasome specifically in primary murine and human macrophages; which are the primary target of ibrutinib in vivo in the setting of metabolic inflammation. Conclusions and Implications In the present study we provide ‘proof of concept' evidence that BTK is a novel therapeutic target for the treatment of diet ‐metabolic inflammation. Ibrutinib may be a candidate for drug repurposing as an anti‐inflammatory for the treatment of metabolic inflammation in T2D and microvascular disease