Obesity and FTO: Changing Focus at a Complex Locus.

The fat mass and obesity-associated (FTO) gene was placed center stage when common intronic variants within the gene were robustly associated with human obesity. Murine models of perturbed Fto expression have shown effects on body weight and composition. However, a clear understanding of the link between FTO intronic variants and FTO activity has remained elusive. Two recent reports now indicate that obesity-associated SNPs appear functionally connected not with FTO but with two neighboring genes: IRX3 and RPGRIP1L. Here, we review these new findings and consider the implications for future analysis of GWAS hits.This is the author accepted manuscript. The final version is available from Cell Press via http://dx.doi.org/10.1016/j.cmet.2014.09.01

FTO is necessary for the induction of leptin resistance by high-fat feeding.

OBJECTIVE: Loss of function FTO mutations significantly impact body composition in humans and mice, with Fto-deficient mice reported to resist the development of obesity in response to a high-fat diet (HFD). We aimed to further explore the interactions between FTO and HFD and determine if FTO can influence the adverse metabolic consequence of HFD. METHODS: We studied mice deficient in FTO in two well validated models of leptin resistance (HFD feeding and central palmitate injection) to determine how Fto genotype may influence the action of leptin. Using transcriptomic analysis of hypothalamic tissue to identify relevant pathways affected by the loss of Fto, we combined data from co-immunoprecipitation, yeast 2-hybrid and luciferase reporter assays to identify mechanisms through which FTO can influence the development of leptin resistant states. RESULTS: Mice deficient in Fto significantly increased their fat mass in response to HFD. Fto (+/-) and Fto (-/-) mice remained sensitive to the anorexigenic effects of leptin, both after exposure to a HFD or after acute central application of palmitate. Genes encoding components of the NFкB signalling pathway were down-regulated in the hypothalami of Fto-deficient mice following a HFD. When this pathway was reactivated in Fto-deficient mice with a single low central dose of TNFα, the mice became less sensitive to the effect of leptin. We identified a transcriptional coactivator of NFкB, TRIP4, as a binding partner of FTO and a molecule that is required for TRIP4 dependent transactivation of NFкB. CONCLUSIONS: Our study demonstrates that, independent of body weight, Fto influences the metabolic outcomes of a HFD through alteration of hypothalamic NFкB signalling. This supports the notion that pharmacological modulation of FTO activity might have the potential for therapeutic benefit in improving leptin sensitivity, in a manner that is influenced by the nutritional environment.The authors thank Roger Cox (MRC Harwell) for kindly providing us with the Fto-deficient mouse strain. This study was supported by the Medical Research Council (MRC) Metabolic Disease Unit (MRC_MC_UU_12012/1), EU FP7- FOOD- 266408 Full4Health and the Helmholtz Alliance ICEMED.This is the final published version. It first appeared at http://www.sciencedirect.com/science/article/pii/S2212877815000241#

Adult onset global loss of the fto gene alters body composition and metabolism in the mouse.

The strongest BMI-associated GWAS locus in humans is the FTO gene. Rodent studies demonstrate a role for FTO in energy homeostasis and body composition. The phenotypes observed in loss of expression studies are complex with perinatal lethality, stunted growth from weaning, and significant alterations in body composition. Thus understanding how and where Fto regulates food intake, energy expenditure, and body composition is a challenge. To address this we generated a series of mice with distinct temporal and spatial loss of Fto expression. Global germline loss of Fto resulted in high perinatal lethality and a reduction in body length, fat mass, and lean mass. When ratio corrected for lean mass, mice had a significant increase in energy expenditure, but more appropriate multiple linear regression normalisation showed no difference in energy expenditure. Global deletion of Fto after the in utero and perinatal period, at 6 weeks of age, removed the high lethality of germline loss. However, there was a reduction in weight by 9 weeks, primarily as loss of lean mass. Over the subsequent 10 weeks, weight converged, driven by an increase in fat mass. There was a switch to a lower RER with no overall change in food intake or energy expenditure. To test if the phenotype can be explained by loss of Fto in the mediobasal hypothalamus, we sterotactically injected adeno-associated viral vectors encoding Cre recombinase to cause regional deletion. We observed a small reduction in food intake and weight gain with no effect on energy expenditure or body composition. Thus, although hypothalamic Fto can impact feeding, the effect of loss of Fto on body composition is brought about by its actions at sites elsewhere. Our data suggest that Fto may have a critical role in the control of lean mass, independent of its effect on food intake

Spatial heterogeneity and peptide availability determine CTL killing efficiency in vivo

The rate at which a cytotoxic T lymphocyte (CTL) can survey for infected cells is a key ingredient of models of vertebrate immune responses to intracellular pathogens. Estimates have been obtained using in vivo cytotoxicity assays in which peptide-pulsed splenocytes are killed by CTL in the spleens of immunised mice. However the spleen is a heterogeneous environment and splenocytes comprise multiple cell types. Are some cell types intrinsically more susceptible to lysis than others? Quantitatively, what impacts are made by the spatial distribution of targets and effectors, and the level of peptide-MHC on the target cell surface? To address these questions we revisited the splenocyte killing assay, using CTL specific for an epitope of influenza virus. We found that at the cell population level T cell targets were killed more rapidly than B cells. Using modeling, quantitative imaging and in vitro killing assays we conclude that this difference in vivo likely reflects different migratory patterns of targets within the spleen and a heterogeneous distribution of CTL, with no detectable difference in the intrinsic susceptibilities of the two populations to lysis. Modeling of the stages involved in the detection and killing of peptide-pulsed targets in vitro revealed that peptide dose influenced the ability of CTL to form conjugates with targets but had no detectable effect on the probability that conjugation resulted in lysis, and that T cell targets took longer to lyse than B cells. We also infer that incomplete killing in vivo of cells pulsed with low doses of peptide may be due to a combination of heterogeneity in peptide uptake and the dissociation, but not internalisation, of peptide-MHC complexes. Our analyses demonstrate how population-averaged parameters in models of immune responses can be dissected to account for both spatial and cellular heterogeneity

Embryogenesis in Sedum acre L.: structural and immunocytochemical aspects of suspensor development

The changes in the formation of both the actin and the microtubular cytoskeleton during the differentiation of the embryo-suspensor in Sedum acre were studied in comparison with the development of the embryo-proper. The presence and distribution of the cytoskeletal elements were examined ultrastructurally and with the light microscope using immunolabelling and rhodamine-phalloidin staining. At the globular stage of embryo development extensive array of actin filaments is present in the cytoplasm of basal cell, the microfilament bundles generally run parallel to the long axis of basal cell and pass in close to the nucleus. Microtubules form irregular bundles in the cytoplasm of the basal cell. A strongly fluorescent densely packed microtubules are present in the cytoplasmic layer adjacent to the wall separating the basal cell from the first layer of the chalazal suspensor cells. At the heart-stage of embryo development, in the basal cell, extremely dense arrays of actin materials are located near the micropylar and chalazal end of the cell. At this stage of basal cell formation, numerous actin filaments congregate around the nucleus. In the fully differentiated basal cell and micropylar haustorium, the tubulin cytoskeleton forms a dense prominent network composed of numerous cross-linked filaments. In the distal region of the basal cell, a distinct microtubular cytoskeleton with numerous microtubules is observed in the cytoplasmic layer adjacent to the wall, separating the basal cell from the first layer of the chalazal suspensor cells. The role of cytoskeleton during the development of the suspensor in S. acre is discussed

Managing patients with ICD shocks and programming tachycardia therapies during acute heart failure syndromes

We review the pharmacologic, interventional and device programming treatment options for patients with implantable cardioverter-defibrillators who present with acute heart failure and implantable cardioverter-defibrillator shocks

Decrease in the production of beta-amyloid by berberine inhibition of the expression of beta-secretase in HEK293 cells

<p>Abstract</p> <p>Background</p> <p>Berberine (BER), the major alkaloidal component of <it>Rhizoma coptidis</it>, has multiple pharmacological effects including inhibition of acetylcholinesterase, reduction of cholesterol and glucose levels, anti-inflammatory, neuroprotective and neurotrophic effects. It has also been demonstrated that BER can reduce the production of beta-amyloid_40/42, which plays a critical and primary role in the pathogenesis of Alzheimer's disease. However, the mechanism by which it accomplishes this remains unclear.</p> <p>Results</p> <p>Here, we report that BER could not only significantly decrease the production of beta-amyloid_40/42and the expression of beta-secretase (BACE), but was also able to activate the extracellular signal-regulated kinase1/2 (ERK1/2) pathway in a dose- and time-dependent manner in HEK293 cells stably transfected with APP695 containing the Swedish mutation. We also find that U0126, an antagonist of the ERK1/2 pathway, could abolish (1) the activation activity of BER on the ERK1/2 pathway and (2) the inhibition activity of BER on the production of beta-amyloid_40/42and the expression of BACE.</p> <p>Conclusion</p> <p>Our data indicate that BER decreases the production of beta-amyloid_40/42by inhibiting the expression of BACE via activation of the ERK1/2 pathway.</p

The relationship between perceived service quality and patient willingness to recommend at a national oncology hospital network

<p>Abstract</p> <p>Background</p> <p>"Willingness to recommend" questions are being increasingly used to measure and manage patient loyalty. Yet, there is little data in the literature correlating the "willingness to recommend" question with commonly used perceived service quality items in surveys to identify the key drivers of the optimal patient experience. We therefore evaluated the relationship between perceived service quality and subsequent single top box "willingness to recommend" scores among oncology patients.</p> <p>Methods</p> <p>A total of 2018 returning cancer patients treated at Cancer Treatment Centers of America^®(CTCA) responded to an internally developed service quality questionnaire, which covered the following dimensions: operations and services, treatment and care with a multidisciplinary team and patient endorsements. Items were measured on a 7-point Likert-type scale ranging from "completely dissatisfied" to "completely satisfied." Patient willingness to, "recommend this facility to friends and associates" was measured on an 11-point scale ranging from "not at all likely" to "extremely likely", which was subsequently dichotomized into two categories: top box response (10) versus all others (0-9). The relationship between perceived service quality and "willingness to recommend" was assessed via Kendall's tau b correlation and univariate and multivariate logistic regression.</p> <p>Results</p> <p>Of the 2018 patients, 959 were newly diagnosed while 1059 were previously treated. 902 were males and 1116 females. The mean age was 54.2 years and the most frequent diagnoses were breast (412), lung (294), prostate (260), colorectal (179) and pancreas (169). 1553 patients said they were "extremely likely" to recommend CTCA to friends and associates, resulting in 77% "top box" responses while 465 (23%) responded in all other categories. The key service quality drivers that were statistically significant in the final logistic model were "team helping you understand your medical condition", "staff genuinely caring for you as an individual", "whole person approach to patient care" and "CTCA medical oncologist."</p> <p>Conclusions</p> <p>In this multi-center study, we demonstrate the predictive significance of perceived service quality as it relates to patient willingness to recommend an oncology service provider. This study is unique in reporting on the role of perceived service quality as a predictor of patient willingness to recommend in a large sample of cancer patients.</p

The study on the outsourcing of Taiwan's hospitals: a questionnaire survey research

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to assess the outsourcing situation in Taiwanese hospitals and compares the differences in hospital ownership and in accreditation levels.</p> <p>Methods</p> <p>This research combined two kinds of methods: a questionnaire survey and the in-depth interview to two CEOs of the sample hospitals. One hospital is not-for-profit, while the other is a public hospital and the research samples are from the hospital data from Taiwan's 2005 to 2007 Department of Health qualifying lists of hospital accreditation. The returned questionnaires were analyzed with STATISTICA^®7.1 version software.</p> <p>Results</p> <p>The results for non-medical items showed medical waste and common trash both have the highest rate (94.6 percent) of being outsourced. The gift store (75 percent) and linen (73 percent) follow close behind, while the lowest rate of outsourcing is in utility maintenance (13.5 percent). For medical items, the highest rate of outsourcing is in the ambulance units (51.4 percent), while the hemodialysis center follows close behind with a rate of 50 percent. For departments of nutrition, pharmacy, and nursing however, the outsourcing rate is lower than 3 percent. This shows that Taiwan's hospitals are still conservative in their willingness to outsource for medical items. The results of the satisfaction paired t-test show that the non-medical items have a higher score than the medical items. The factor analysis showed the three significant factors in of non medical items' outsourcing are "performance", "finance", and "human resource". For medical items, the two factors are "operation" and satisfaction". To further exam the factor validity and reliability of the satisfaction model, a confirmative factor analysis (CFA) was conducted using structure equation modeling (SEM) method and found the model fitting well.</p> <p>Conclusion</p> <p>Hospitals, especially for public hospitals, can get benefits from outsourcing to revive the full-time-equivalent and human resource limitation.</p

Patterns of HIV prevalence among injecting drug users in the cross-border area of Lang Son Province, Vietnam, and Ning Ming County, Guangxi Province, China

BACKGROUND: To assess patterns of injecting drug use and HIV prevalence among injecting drug users (IDUs) in an international border area along a major heroin trans-shipment route. METHODS: Cross-sectional surveys of IDUs in 5 sites in Lang Son Province, Vietnam (n = 348) and 3 sites in Ning Ming County, Guangxi Province, China (n = 308). Respondents were recruited through peer referral ("snowball") methods in both countries, and also from officially recorded lists of IDUs in Vietnam. A risk behavior questionnaire was administered and HIV counseling and testing conducted. RESULTS: Participants in both countries were largely male, in their 20s, and unmarried. A majority of subjects in both countries were members of ethnic minority groups. There were strong geographic gradients for length of drug injecting and for HIV seroprevalence. Both mean years injecting and HIV seroprevalence declined from the Vietnamese site farthest from the border to the Chinese site farthest from the border. 10.6% of participants in China and 24.5% of participants in Vietnam reported crossing the international border in the 6 months prior to interview. Crossing the border by IDUs was associated with (1) distance from the border, (2) being a member of an ethnic minority group, and (3) being HIV seropositive among Chinese participants. CONCLUSION: Reducing the international spread of HIV among IDUs will require programs at the global, regional, national, and "local cross border" levels. At the local cross border level, the programs should be coordinated on both sides of the border and on a sufficient scale that IDUs will be able to readily obtain clean injection equipment on the other side of the border as well as in their country of residence