FNDC5 attenuates adipose tissue inflammation and insulin resistance via AMPK-mediated macrophage polarization in obesity

BackgroundObesity-induced chronic inflammation is critical in the pathogenesis of insulin resistance, and the recruitment and proinflammatory activation of adipose tissue macrophages (ATMs) is important for the development of this process. Here, we examined the effects of fibronectin type III domain-containing 5 (FNDC5) on inflammation and insulin resistance in high-fat diet-induced obese mice.Materials and MethodsMale wild-type (WT) and FNDC5^−/− mice were fed with standard chow (Ctrl) or high fat diet (HFD) for 20 weeks to induce obesity and insulin resistance. Firstly, effects of FNDC5 gene deletion on obesity, insulin resistance, macrophage accumulation and polarization and adipose tissue inflammation were determined in mice. Secondly, the macrophage polarity shift was further examined with flow cytometry in isolated stromal vascular fraction (SVF). Thirdly, the effects of exogenous FNDC5 on lipopolysaccharide (LPS)-induced macrophage polarization, inflammation and the underlying signaling mechanism were investigated in RAW264.7 macrophages and primary mouse peritoneal cavity macrophages (PMs). Finally, the therapeutic effects of FNDC5 overexpression were examined in HFD-induced obese WT and FNDC5^−/− mice.ResultsFNDC5 gene deletion aggravated obesity, insulin resistance, fat accumulation and inflammation accompanied with enhanced AMPK inhibition, macrophages recruitment and M1 polarization in mice fed with HFD. Exogenous FNDC5 inhibited LPS-induced M1 macrophage polarization and inflammatory cytokine production via AMPK phosphorylation in both RAW264.7 macrophages and PMs. FNDC5 overexpression attenuated insulin resistance, AMPK inhibition, M1 macrophage polarization and inflammatory cytokine production in adipose tissue of obese WT and FNDC5^−/− mice.ConclusionsFNDC5 attenuates adipose tissue inflammation and insulin resistance via AMPK-mediated macrophage polarization in HFD-induced obesity. FNDC5 plays several beneficial roles in obesity and may be used as a therapeutic regimen for preventing inflammation and insulin resistance in obesity and diabetes.     

A tissue stabilization device for MRI-guided breast biopsy

We present a breast tissue stabilization device that can be used in magnetic resonance imaging-guided biopsy. The device employs adjustable support plates with an optimized geometry to minimize the biopsy target displacement using smaller compression than the conventional parallel plates approach. It is expected that the reduced compression will cause less patient discomfort and improve image quality by enhancing the contrast intake. Precomputed optimal positions of the stabilization plates for a given biopsy target location are provided in a look-up table. The results of several experiments with a prototype of the device carried out on chicken breast tissue demonstrate the effectiveness of the new design when compared with conventional stabilization methods. The proposed stabilization mechanism provides excellent flexibility in selecting the needle insertion point and can be used in manual as well as robot-assisted biopsy procedures.     

Speech outcomes at 5 and 10 years of age after one-stage palatal repair with muscle reconstruction in children born with isolated cleft palate

Background: The aim of this study was to investigate speech outcomes in children with clefts in the hard and/or soft palate only (CPH/CPS), in order to determine the prevalence of cleft speech characteristics, the change between 5 and 10?years of age, and the difference in occurrence between CPH and CPS.

Methods: A consecutive series of 88 children born with CPH or CPS were included in a retrospective cohort. All participants were treated with one-stage palatal repair using a minimal incision technique with muscle reconstruction (mean age 13?months). Twelve children (14%) received a velopharyngeal flap. Cleft speech variables were rated at 5 and 10?years of age independently by three experienced external speech-language pathologists. Inter- and intra-rater agreements were determined, and the prevalence of cleft speech characteristics was calculated.

Results: Moderate-to-severe hypernasality and weak pressure consonants were present in 5%–10% of the children at 5?years, with marginal but statistically significant improvement at 10?years of age. Frequently or always occurring audible nasal air leakage was detected in 20% of children at age 5, and increased to ～35% of the children at 10?years. Ten per cent had compensatory articulation at age 5, and 25% demonstrated s-distortions, whereas few had these problems at age 10.

Conclusions: The results demonstrate low occurrence of compensatory articulation problems in this cohort, even by 5?years of age. The high presence of symptoms of velopharyngeal insufficiency at 10?years of age suggests a need for additional secondary velopharyngeal surgery.     

Folinic Acid Supplementation in Higher Doses is Associated with Graft Rejection in Pediatric Hematopoietic Stem Cell Transplantation

Folinic acid is widely used in hematopoietic stem cell transplantation (SCT), mainly to reverse antifolate effects of such drugs as methotrexate and cotrimoxazole but also empirically to reduce toxicity and support hematopoietic recovery. However, concerns have been raised in oncohematology about reduced curative rates associated with folinic acid administration. The clinical impact of folinic acid with regard to graft-versus-host disease (GVHD), relapse, and rejection in pediatric SCT is largely undetermined. In this single-center retrospective study we investigated folinic acid administration in 87 children undergoing SCT between 2007 and 2010. Data on folinic acid dosage and duration were analyzed along with SCT parameters using univariate and multivariate statistics. Folinic acid treatment was not correlated with relapse or GVHD grades ≥ II. However, significantly higher folinic acid doses until day +21 post-SCT had been administered to patients rejecting their grafts (P < .005). In a subanalysis of nonmalignant disease and reduced-intensity conditioning (RIC) SCTs, higher total folinic acid doses were found to be associated with rejection (P = .015 and P = .026). Multivariate analysis identified RIC (odds ratio, 19.9; P < .01) and an early total folinic acid dose of >185 mg/m² (odds ratio, 11.4; P = .03) as risk factors for graft rejection. Late folinic acid treatment had no impact on relapse, GVHD, and rejection. To conclude, administration of folinic acid in pediatric SCT seems safe in terms of relapse and GVHD. However, it should be carried out with caution, especially in patients with nonmalignant conditions and those receiving RIC to avoid graft rejection.     

Social network influences on smoking,drinking and drug use in secondary school: centrifugal and centripetal forces

We explore how school experiences and social networks structure young people’s substance use in different institutional contexts. The concepts of ‘selection’ and ‘influence’ are situated within the context of bounded agency, counter‐school cultures and Bourdieusian notions of capital. We employed individual and group interviews, network‐mapping, and observations at two contrasting English secondary schools. Both schools were characterised by extended social network structures that appeared to influence patterns of substance use, although the mechanisms via which this occurred varied according to school context. At Grange House school (suburban context) a minority of students from disadvantaged families were alienated by the attainment‐focused regime, marginalised by a strong peer‐led centrifugal force pushing them outwards, and substance use was an alternative source of bonding and identity for these students. In contrast, at North Street a centripetal force operated whereby the majority of students were pulled towards highly‐visible, normative markers of ‘safe’, ‘road culture’, such as cannabis use and gang‐involvement, as they attempted to fit in and survive in an inner‐city school environment. We conclude that health inequalities may be reproduced through these distinctive centrifugal and centripetal forces in different institutional contexts, and this should be the focus of quantitative examination in the UK and elsewhere.