Magnetization transfer imaging in ‘premanifest’ Huntington’s disease

To investigate whether magnetization transfer imaging (MTI) is a useful detector of diffuse brain abnormalities in ‘premanifest’ carriers of the Huntington’s disease (HD) gene mutation. Furthermore we examined the relations between MTI, clinical measures and CAG repeat length. Sixteen premanifest carriers of the HD gene without motor manifestation and 14 non-carriers underwent a clinical evaluation and a MRI scan. MTI analysis of whole brain, grey matter and white matter was performed producing magnetization transfer ratio (MTR) histograms. A lower peak height of the grey matter MTR histogram in carriers was significantly associated with more UHDRS motor abnormalities. Furthermore, a lower peak height of the whole brain, grey and white matter was strongly associated with a longer CAG repeat length. MTI measures themselves did not differ significantly between carriers and non-carriers. In premanifest HD mutation carriers, a lower MTR peak height, reflecting worse histological brain composition, was related to subtle motor abnormalities and higher CAG repeat length. Although we could not detect altered MTI characteristics in carriers of the HD gene mutation without clinical manifestations, we did provide evidence that the MTR peak height might reflect genetic and subclinical disease burden and may be of value in monitoring further disease progression and provide insight in clinical heterogeneity

Role of Fibronectin in the Adhesion of Acinetobacter baumannii to Host Cells

Adhesion to host cells is an initial and important step in Acinetobacter baumannii pathogenesis. However, there is relatively little information on the mechanisms by which A. baumannii binds to and interacts with host cells. Adherence to extracellular matrix proteins, such as fibronectin, affords pathogens with a mechanism to invade epithelial cells. Here, we found that A. baumannii adheres more avidly to immobilized fibronectin than to control protein. Free fibronectin used as a competitor resulted in dose-dependent decreased binding of A. baumannii to fibronectin. Three outer membrane preparations (OMPs) were identified as fibronectin binding proteins (FBPs): OMPA, TonB-dependent copper receptor, and 34 kDa OMP. Moreover, we demonstrated that fibronectin inhibition and neutralization by specific antibody prevented significantly the adhesion of A. baumannii to human lung epithelial cells (A549 cells). Similarly, A. baumannii OMPA neutralization by specific antibody decreased significantly the adhesion of A. baumannii to A549 cells. These data indicate that FBPs are key adhesins that mediate binding of A. baumannii to human lung epithelial cells through interaction with fibronectin on the surface of these host cells

Dual-Wavelength Imaging of Tumor Progression by Activatable and Targeting Near-Infrared Fluorescent Probes in a Bioluminescent Breast Cancer Model

Bioluminescence imaging (BLI) has shown its appeal as a sensitive technique for in vivo whole body optical imaging. However, the development of injectable tumor-specific near-infrared fluorescent (NIRF) probes makes fluorescence imaging (FLI) a promising alternative to BLI in situations where BLI cannot be used or is unwanted (e.g., spontaneous transgenic tumor models, or syngeneic mice to study immune effects)

Leptin Contributes to the Adaptive Responses of Mice to High-Fat Diet Intake through Suppressing the Lipogenic Pathway

Background: Leptin is an adipocyte-derived hormone that plays a critical role in energy homeostasis and lipid metabolism. Overnutrition-associated obesity is known to be accompanied by hyperleptinemia. However, the physiological actions of leptin in the metabolic responses to high-fat diet (HFD) intake remain to be completely elucidated. Here we characterized the metabolic features of mice fed high-fat diets and investigated the impact of leptin upon the lipogenic program which was found to be suppressed by HFD feeding through a proteomics approach. Results: When maintained on two types of high-fat diets for up to 16 weeks, mice with a higher fat intake exhibited increased body fat accumulation at a greater pace, developing more severely impaired glucose tolerance. Notably, HFD feeding at 4 weeks elicited the onset of marked hyperleptinemia, prior to the occurrence of apparent insulin resistance and hyperinsulinemia. Proteomic analysis revealed dramatically decreased expression of lipogenic enzymes in the white adipose tissue (WAT) from HFD-fed mice, including ATP-citrate lyase (ACL) and fatty acid synthase (FAS). The expression of ACL and FAS in the liver was similarly suppressed in response to HFD feeding. By contrast, HFD-induced downregulation of hepatic ACL and FAS was significantly attenuated in leptin receptor-deficient db/db mice. Furthermore, in the liver and WAT of wild type animals, intraperitoneal leptin administration was able to directly suppress the expression of these two lipogenic enzymes, accompanied by reduced triglyceride levels both in the liver and serum. Conclusions: These results suggest that leptin contributes to the metabolic responses in adaptation to overnutrition through suppressing the expression of lipogenic enzymes, and that the lipogenic pathway represents a key targeted peripheral component in exerting leptin's liporegulatory actions. © 2009 Jiang et al

Molecular changes in the expression of human colonic nutrient transporters during the transition from normality to malignancy

Healthy colonocytes derive 60–70% of their energy supply from short-chain fatty acids, particularly butyrate. Butyrate has profound effects on differentiation, proliferation and apoptosis of colonic epithelial cells by regulating expression of various genes associated with these processes. We have previously shown that butyrate is transported across the luminal membrane of the colonic epithelium via a monocarboxylate transporter, MCT1. In this paper, using immunohistochemistry and in situ hybridisation histochemistry, we have determined the profile of MCT1 protein and mRNA expression along the crypt to surface axis of healthy human colonic tissue. There is a gradient of MCT1 protein expression in the apical membrane of the cells along the crypt-surface axis rising to a peak in the surface epithelial cells. MCT1 mRNA is expressed along the crypt-surface axis and is most abundant in cells lining the crypt. Analysis of healthy colonic tissues and carcinomas using immunohistochemistry and Western blotting revealed a significant decline in the expression of MCT1 protein during transition from normality to malignancy. This was reflected in a corresponding reduction in MCT1 mRNA expression, as measured by Northern analysis. Carcinoma samples displaying reduced levels of MCT1 were found to express the high affinity glucose transporter, GLUT1, suggesting that there is a switch from butyrate to glucose as an energy source in colonic epithelia during transition to malignancy. The expression levels of MCT1 in association with GLUT1 could potentially be used as determinants of the malignant state of colonic tissue

Raising AWaRe-ness of antimicrobial stewardship challenges in pediatric emergency care: results from the PERFORM study assessing consistency and appropriateness of antibiotic prescribing across Europe.

OBJECTIVES Optimization of antimicrobial stewardship (AMS) is key to tackling antimicrobial resistance (AMR), which is exacerbated by over-prescription of antibiotics in pediatric Emergency Departments (EDs). We described patterns of empiric antibiotic use in European EDs, and characterized appropriateness and consistency of prescribing. METHODS Between August 2016 and December 2019 febrile children attending the ED in nine European countries with suspected infection were recruited into the PERFORM (Personalised Risk assessment in Febrile illness to Optimise Real-life Management) study. Empiric systemic antibiotic use was determined in view of assigned final 'bacterial' or 'viral' phenotype. Antibiotics were classified according to WHO AWaRe. RESULTS Of 2130 febrile episodes (excluding children with non-bacterial/non-viral phenotypes), 1549 (72.7%) were assigned a 'bacterial' and 581 (27.3%) a 'viral' phenotype. A total of 1318/1549 (85.1%) episodes with a 'bacterial' and 269/581 (46.3%) with a 'viral' phenotype received empiric systemic antibiotics (first two days of admission). Of those, the majority (87.8% in 'bacterial' and 87.0% in 'viral' group) received parenteral antibiotics. The top three antibiotics prescribed were third-generation cephalosporins, penicillins and penicillin/beta-lactamase inhibitor combinations. Of those treated with empiric systemic antibiotics in the 'viral' group 216/269 (80.3%) received ≥ one Watch antibiotic. CONCLUSIONS Differentiating bacterial from viral etiology in febrile illness on initial ED presentation remains challenging, resulting in a substantial over-prescription of antibiotics. A significant proportion of patients with a 'viral' phenotype received systemic antibiotics, predominantly classified as WHO Watch. Rapid and accurate point-of-care tests in the ED differentiating between bacterial and viral etiology, could significantly improve AMS

High-Fat Diet Induces Apoptosis of Hypothalamic Neurons

Consumption of dietary fats is amongst the most important environmental factors leading to obesity. In rodents, the consumption of fat-rich diets blunts leptin and insulin anorexigenic signaling in the hypothalamus by a mechanism dependent on the in situ activation of inflammation. Since inflammatory signal transduction can lead to the activation of apoptotic signaling pathways, we evaluated the effect of high-fat feeding on the induction of apoptosis of hypothalamic cells. Here, we show that consumption of dietary fats induce apoptosis of neurons and a reduction of synaptic inputs in the arcuate nucleus and lateral hypothalamus. This effect is dependent upon diet composition, and not on caloric intake, since pair-feeding is not sufficient to reduce the expression of apoptotic markers. The presence of an intact TLR4 receptor, protects cells from further apoptotic signals. In diet-induced inflammation of the hypothalamus, TLR4 exerts a dual function, on one side activating pro-inflammatory pathways that play a central role in the development of resistance to leptin and insulin, and on the other side restraining further damage by controlling the apoptotic activity

Fyn Mediates Leptin Actions in the Thymus of Rodents

BACKGROUND:Several effects of leptin in the immune system rely on its capacity to modulate cytokine expression and apoptosis in the thymus. Surprisingly, some of these effects are dependent on signal transduction through the IRS1/PI3-kinase, but not on the activation of JAK2. Since all the well known effects of leptin in different cell types and tissues seem to be dependent on JAK2 activation, we hypothesized that, at least for the control of thymic function, another, unknown kinase could mediate the transduction of the leptin signal from the ObR towards the IRS1/PI3-kinase signaling cascade. METHODOLOGY/PRINCIPAL FINDINGS:Here, by employing immunoblot, real-time PCR and flow citometry we show that the tyrosine kinase, Fyn, is constitutively associated with the ObR in thymic cells. Following a leptin stimulus, Fyn undergoes an activating tyrosine phosphorylation and a transient association with IRS1. All these effects are independent of JAK2 activation and, upon Fyn inhibition, the signal transduction towards IRS1/PI3-kinase is abolished. In addition, the inhibition of Fyn significantly modifies the effects of leptin on thymic cytokine expression. CONCLUSION/SIGNIFICANCE:Therefore, in the thymus, Fyn acts as a tyrosine kinase that transduces the leptin signal independently of JAK2 activation, and mediates some of the immunomodulatory effects of leptin in this tissue