22 CFR Appendix I to Part 211 - Operational Plan

Code of Federal Regulations, 2013 CFR

2013-04-01

... for the selection of the geographical areas where programs will be carried out; the calculation of... extension services. Describe specific areas of collaboration relative to program purposes. (6) Monitoring...) and (b), will be met. 5. Logistics. Provide a logistics plan that demonstrates the adequacy and...

Prebiotics in the management of components of the metabolic syndrome.

PubMed

O'Connor, Sarah; Chouinard-Castonguay, Sarah; Gagnon, Claudia; Rudkowska, Iwona

2017-10-01

Components of the metabolic syndrome (MetS), including abdominal obesity, low-grade chronic systemic inflammation, altered glucose metabolism, dyslipidemia and high blood pressure, are major threats to healthy aging in modern societies. The connection between MetS components and gut microflora is now acknowledged and multiple therapeutic strategies have been proposed to change the composition of the gut microbiota in order to promote optimal metabolic health. Prebiotics have the ability to favour growth of beneficial bacteria, especially short-chain fatty-acids (SCFA) producers. Increased SCFA in the gut is associated with improved satiety and weight loss, reduced systemic inflammation by increasing the gut barrier function, and improved glucose and lipid metabolism. The objective of this review is to examine the recent literature in order to determine the types and doses of prebiotics that could be recommended for the management of MetS. A review of the literature was executed using the MEDLINE database and clinical trials from 2013 to 2017 were selected for analysis. In conclusion, a daily supplementation of 10g of inulin, resistant starches or fructo-oligosaccharide-enriched inulin could have beneficial effects on MetS components in individuals with type 2 diabetes. In healthy subjects or in individuals with the MetS, the results are too heterogeneous and scarce to be able to set any specific recommendations. More clinical studies are needed to better understand the role of prebiotics in the management of MetS components. Copyright © 2017 Elsevier B.V. All rights reserved.

Beneficial association between active travel and metabolic syndrome in Latin-America: A cross-sectional analysis from the Chilean National Health Survey 2009-2010.

PubMed

Sadarangani, Kabir P; Von Oetinger, Astrid; Cristi-Montero, Carlos; Cortínez-O'Ryan, Andrea; Aguilar-Farías, Nicolás; Martínez-Gómez, David

2018-02-01

There is limited evidence on potential health benefits of active travel, independently of leisure-time physical activity (PA), with metabolic syndrome (MetS) in Latin-America. To investigate the relationship between active travel and metabolic syndrome (MetS) and its components in a national representative sample of Chilean adults. Cross-sectional study of 2864 randomly selected adults' participants enrolled in the 2009-2010 Chilean National Health Survey (CNHS). Self-reported PA was obtained with the validated Global PA Questionnaire and classifying participants into insufficiently active (<150min/week) or active (≥150min/week). MetS was diagnosed from the modified Adult Treatment Panel (ATP) III criteria with national-specific abdominal obesity cut points. Multilevel logistic regression analysis was applied to estimate associations of travel PA with MetS and its components at a regional level, adjusted for socio-demographic characteristics and other types of PA. 46.2% of the sample engaged in 150min/week of active travel and the prevalence of MetS was 33.7%. Mets was significantly lower among active travel participants. Active travel was associated with lower odds of MetS (OR 0.72; 95%CI 0.61-0.86), triglycerides (OR 0.77; 95%CI 0.64-0.92) and abdominal obesity (OR 0.82; 95%CI 0.69-0.97) after controlling for socio-demographics and other types of PA. Active travel was negatively associated with MetS, triglycerides and abdominal obesity. Efforts to increase regional active travel should be addressed as a measure to prevent and reduce the prevalence of MetS and disease burden in middle income countries. Copyright © 2017 Elsevier Inc. All rights reserved.

Nutraceutical approaches to metabolic syndrome.

PubMed

Sirtori, Cesare R; Pavanello, Chiara; Calabresi, Laura; Ruscica, Massimiliano

2017-12-01

Metabolic Syndrome (MetS), affecting at least 30% of adults in the Western World, is characterized by three out of five variables, from high triglycerides, to elevated waist circumference and blood pressure. MetS is not characterized by elevated cholesterolemia, but is rather the consequence of a complex interaction of factors generally leading to increased insulin resistance. Drug treatments are of difficult handling, whereas well-characterized nutraceuticals may offer an effective alternative. Among these, functional foods, e.g. plant proteins, have been shown to improve insulin resistance and reduce triglyceride secretion. Pro- and pre-biotics, that are able to modify intestinal microbiome, reduce absorption of specific nutrients and improve the metabolic handling of energy-rich foods. Finally, specific nutraceuticals have proven to be of benefit, in particular, red-yeast rice, berberine, curcumin as well as vitamin D. All these can improve lipid handling by the liver as well as ameliorate insulin resistance. While lifestyle approaches, such as with the Mediterranean diet, may prove to be too complex for the single patient, better knowledge of selected nutraceuticals and more appropriate formulations leading to improved bioavailability will certainly widen the use of these agents, already in large use for the management of these very frequent patient groups. Key messages Functional foods, e.g. plant proteins, improve insulin resistance. Pro- and pre-biotics improve the metabolic handling of energy-rich foods. Nutraceutical can offer a significant help in handling MetS patients being part of lifestyle recommendations.

Structural Bioinformatics-Based Prediction of Exceptional Selectivity of p38 MAP Kinase Inhibitor PH-797804

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xing, Li; Shieh, Huey S.; Selness, Shaun R.

2009-07-24

PH-797804 is a diarylpyridinone inhibitor of p38{alpha} mitogen-activated protein (MAP) kinase derived from a racemic mixture as the more potent atropisomer (aS), first proposed by molecular modeling and subsequently confirmed by experiments. On the basis of structural comparison with a different biaryl pyrazole template and supported by dozens of high-resolution crystal structures of p38{alpha} inhibitor complexes, PH-797804 is predicted to possess a high level of specificity across the broad human kinase genome. We used a structural bioinformatics approach to identify two selectivity elements encoded by the TXXXG sequence motif on the p38{alpha} kinase hinge: (i) Thr106 that serves as themore » gatekeeper to the buried hydrophobic pocket occupied by 2,4-difluorophenyl of PH-797804 and (ii) the bidentate hydrogen bonds formed by the pyridinone moiety with the kinase hinge requiring an induced 180{sup o} rotation of the Met109-Gly110 peptide bond. The peptide flip occurs in p38{alpha} kinase due to the critical glycine residue marked by its conformational flexibility. Kinome-wide sequence mining revealed rare presentation of the selectivity motif. Corroboratively, PH-797804 exhibited exceptionally high specificity against MAP kinases and the related kinases. No cross-reactivity was observed in large panels of kinase screens (selectivity ratio of >500-fold). In cellular assays, PH-797804 demonstrated superior potency and selectivity consistent with the biochemical measurements. PH-797804 has met safety criteria in human phase I studies and is under clinical development for several inflammatory conditions. Understanding the rationale for selectivity at the molecular level helps elucidate the biological function and design of specific p38{alpha} kinase inhibitors.« less

The positive effects of a peer-led intervention system for individuals with a risk of metabolic syndrome.

PubMed

Sanee, Aree; Somrongthong, Ratana; Plianbangchang, Samlee

2017-01-01

Metabolic syndrome (MetS) is a major health risk in Thailand. Although it is reported that females have a higher rate of MetS than males, very few peer-led intervention studies have been conducted on specific groups, such as seamstresses, at risk of MetS. This study aimed to evaluate the effect of a peer-led intervention program on reducing MetS risk factors in individuals working in Thai Uniform Sewing Military Factories. A quasiexperimental program was introduced using a pre- and posttest design that was applied to female sewing factory workers selected for this research. All participants had at least one of the key MetS symptoms. The experimental group (N=50 participants) received 12 weekly peer-led individual support discussion sessions that included both dietary and physical activity (PA) advice and the control group (N=50 participants) followed their usual daily routines. The Student's t -test and the Pearson's chi-squared test were used to compare the differences of baseline data and analysis of variance was used for analysis of the data after intervention. The results showed that after 3 months of participation, when compared to the control group, the experimental group had significantly improved systolic blood pressure (BP) ( P =0.04), diastolic BP ( P <0.001), PA ( P =0.05), knowledge scores of MetS, perception of MetS and risk factors ( P <0.001), and stress assessment ( P =0.002). Waist circumference, body mass index, and Food Frequency Questionnaire score were not significantly different but still improved. Findings from this study suggest that a peer-led support program can be introduced as an effective means of improving the behaviors of mostly sedentary factory workers at risk of MetS caused by working habits that are detrimental to health.

Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior.

PubMed

Thompson, Barbara L; Levitt, Pat

2015-01-01

Our laboratory discovered that the gene encoding the receptor tyrosine kinase, MET, contributes to autism risk. Expression of MET is reduced in human postmortem temporal lobe in autism and Rett Syndrome. Subsequent studies revealed a role for MET in human and mouse functional and structural cortical connectivity. To further understand the contribution of Met to brain development and its impact on behavior, we generated two conditional mouse lines in which Met is deleted from select populations of central nervous system neurons. Mice were then tested to determine the consequences of disrupting Met expression. Mating of Emx1 (cre) and Met (fx/fx) mice eliminates receptor signaling from all cells arising from the dorsal pallium. Met (fx/fx) and Nestin (cre) crosses result in receptor signaling elimination from all neural cells. Behavioral tests were performed to assess cognitive, emotional, and social impairments that are observed in multiple neurodevelopmental disorders and that are in part subserved by circuits that express Met. Met (fx/fx) /Emx1 (cre) null mice displayed significant hypoactivity in the activity chamber and in the T-maze despite superior performance on the rotarod. Additionally, these animals showed a deficit in spontaneous alternation. Surprisingly, Met (fx/fx; fx/+) /Nestin (cre) null and heterozygous mice exhibited deficits in contextual fear conditioning, and Met (fx/+) /Nestin (cre) heterozygous mice spent less time in the closed arms of the elevated plus maze. These data suggest a complex contribution of Met in the development of circuits mediating social, emotional, and cognitive behavior. The impact of disrupting developmental Met expression is dependent upon circuit-specific deletion patterns and levels of receptor activity.

Sensitivity, specificity, and predictive values of pediatric metabolic syndrome components in relation to adult metabolic syndrome: the Princeton LRC follow-up study.

PubMed

Huang, Terry T-K; Nansel, Tonja R; Belsheim, Allen R; Morrison, John A

2008-02-01

To estimate the sensitivity, specificity, and predictive values of pediatric metabolic syndrome (MetS) components (obesity, fasting glucose, triglycerides, high-density lipoprotein, and blood pressure) at various cutoff points in relation to adult MetS. Data from the National Heart, Lung, and Blood Institute Lipid Research Clinics Princeton Prevalence Study (1973-1976) and the Princeton Follow-up Study (2000-2004) were used to calculate sensitivity, specificity, and positive and negative predictive values for each component at a given cutoff point and for aggregates of components. Individual pediatric components alone showed low to moderate sensitivity, high specificity, and moderate predictive values in relation to adult MetS. When all 5 pediatric MetS components were considered, the presence of at least 1 abnormality had higher sensitivity for adult MetS than individual components alone. When multiple abnormalities were mandatory for MetS, positive predictive value was high and sensitivity was low. Childhood body mass alone showed neither high sensitivity nor high positive predictive value for adult MetS. Considering multiple metabolic variables in childhood can improve the predictive usefulness for adult MetS, compared with each component or body mass alone. MetS variables may be useful for identifying some children who are at risk for prevention interventions.

Pulmonary actions of the neurokinin1-specific agonist [Sar9,Met(O2)11]-substance P.

PubMed

Yiamouyiannis, C A; Stengel, P W; Cockerham, S L; Silbaugh, S A

1995-01-01

We examined the relationship between airway obstruction and plasma extravasation produced by the intravenous administration of the selective NK1 receptor agonist [Sar9, Met(O2)11]-substance P(SP). Conscious guinea-pigs were injected with Evans' blue dye followed by intravenous [Sar9,Met(O2)11]-SP. Animals were killed 3 min later and airway obstruction, determined via excised lung gas volumes, and plasma extravasation in the trachea, mainstem bronchi and intrapulmonary airways quantitated. Maximal plasma protein extravasation occurred at a dose about 30 times less than that required to elicit airway obstruction. Neither the neutral endopeptidase (NEP) inhibitor, thiorphan, or the angiotensin-converting enzyme (ACE) inhibitor, captopril, altered the extravasation response to [Sar9,Met(O2)11]-SP. However, thiorphan alone or combined with captopril produced a small but significant potentiation of the airway obstructive response. The marked difference between pulmonary gas trapping and Evans' blue extravasation responses suggest that [Sar9,Met(O2)11]-SP-induced airway obstruction is not secondary to increased pulmonary edema.

Optimization of multi-environment trials for genomic selection based on crop models.

PubMed

Rincent, R; Kuhn, E; Monod, H; Oury, F-X; Rousset, M; Allard, V; Le Gouis, J

2017-08-01

We propose a statistical criterion to optimize multi-environment trials to predict genotype × environment interactions more efficiently, by combining crop growth models and genomic selection models. Genotype × environment interactions (GEI) are common in plant multi-environment trials (METs). In this context, models developed for genomic selection (GS) that refers to the use of genome-wide information for predicting breeding values of selection candidates need to be adapted. One promising way to increase prediction accuracy in various environments is to combine ecophysiological and genetic modelling thanks to crop growth models (CGM) incorporating genetic parameters. The efficiency of this approach relies on the quality of the parameter estimates, which depends on the environments composing this MET used for calibration. The objective of this study was to determine a method to optimize the set of environments composing the MET for estimating genetic parameters in this context. A criterion called OptiMET was defined to this aim, and was evaluated on simulated and real data, with the example of wheat phenology. The MET defined with OptiMET allowed estimating the genetic parameters with lower error, leading to higher QTL detection power and higher prediction accuracies. MET defined with OptiMET was on average more efficient than random MET composed of twice as many environments, in terms of quality of the parameter estimates. OptiMET is thus a valuable tool to determine optimal experimental conditions to best exploit MET and the phenotyping tools that are currently developed.

Hepatoma targeting peptide conjugated bio-reducible polymer complexed with oncolytic adenovirus for cancer gene therapy.

PubMed

Choi, Joung-Woo; Kim, Hyun Ah; Nam, Kihoon; Na, Youjin; Yun, Chae-Ok; Kim, SungWan

2015-12-28

Despite adenovirus (Ad) vector's numerous advantages for cancer gene therapy, such as high ability of endosomal escape, efficient nuclear entry mechanism, and high transduction, and therapeutic efficacy, tumor specific targeting and antiviral immune response still remain as a critical challenge in clinical setting. To overcome these obstacles and achieve cancer-specific targeting, we constructed tumor targeting bioreducible polymer, an arginine grafted bio-reducible polymer (ABP)-PEG-HCBP1, by conjugating PEGylated ABP with HCBP1 peptides which has high affinity and selectivity towards hepatoma. The ABP-PEG-HCBP1-conjugated replication incompetent GFP-expressing ad, (Ad/GFP)-ABP-PEG-HCBP1, showed a hepatoma cancer specific uptake and transduction compared to either naked Ad/GFP or Ad/GFP-ABP. Competition assays demonstrated that Ad/GFP-ABP-PEG-HCBP1-mediated transduction was specifically inhibited by HCBP1 peptide rather than coxsackie and adenovirus receptor specific antibody. In addition, ABP-PEG-HCBP1 can protect biological activity of Ad against serum, and considerably reduced both innate and adaptive immune response against Ad. shMet-expressing oncolytic Ad (oAd; RdB/shMet) complexed with ABP-PEG-HCBP1 delivered oAd efficiently into hepatoma cancer cells. The oAd/ABP-PEG-HCBP1 demonstrated enhanced cancer cell killing efficacy in comparison to oAd/ABP complex. Furthermore, Huh7 and HT1080 cancer cells treated with oAd/shMet-ABP-PEG-HCBP1 complex had significantly decreased Met and VEGF expression in hepatoma cancer, but not in non-hepatoma cancer. In sum, these results suggest that HCBP1-conjugated bioreducible polymer could be used to deliver oncolytic Ad safely and efficiently to treat hepatoma. Copyright © 2015 Elsevier B.V. All rights reserved.

Hepatoma targeting peptide conjugated bio-reducible polymer complexed with oncolytic adenovirus for cancer gene therapy

PubMed Central

Choi, Joung-Woo; Kim, Hyun Ah; Nam, Kihoon; Na, Youjin; Yun, Chae-Ok; Kim, SungWan

2015-01-01

Despite adenovirus (Ad) vector’s numerous advantages for cancer gene therapy, such as high ability of endosomal escape, efficient nuclear entry mechanism, and high transduction, and therapeutic efficacy, tumor specific targeting and antiviral immune response still remain as a critical challenge in clinical setting. To overcome these obstacles and achieve cancer-specific targeting, we constructed tumor targeting bioreducible polymer, an arginine grafted bio-reducible polymer (ABP)-PEG-HCBP1, by conjugating PEGylated ABP with HCBP1 peptides which has high affinity and selectivity towards hepatoma. The ABP-PEG-HCBP1-conjugated replication incompetent GFP-expressing ad, (Ad/GFP)-ABP-PEG-HCBP1, showed a hepatoma cancer specific uptake and transduction compared to either naked Ad/GFP or Ad/GFP-ABP. Competition assays demonstrated that Ad/GFP-ABP-PEG-HCBP1-mediated transduction was specifically inhibited by HCBP1 peptide rather than coxsackie and adenovirus receptor specific antibody. In addition, ABP-PEG-HCBP1 can protect biological activity of Ad against serum, and considerably reduced both innate and adaptive immune response against Ad. shMet-expressing oncolytic Ad (oAd; RdB/shMet) complexed with ABP-PEG-HCBP1 delivered oAd efficiently into hepatoma cancer cells. The oAd/ABP-PEG-HCBP1 demonstrated enhanced cancer cell killing efficacy in comparison to oAd/ABP complex. Furthermore, Huh7 and HT1080 cancer cells treated with oAd/shMet-ABP-PEG-HCBP1 complex had significantly decreased Met and VEGF expression in hepatoma cancer, but not in non-hepatoma cancer. In sum, these results suggest that HCBP1-conjugated bioreducible polymer could be used to deliver oncolytic Ad safely and efficiently to treat hepatoma. PMID:26437261

Metabolic syndrome, major depression, generalized anxiety disorder, and ten-year all-cause and cardiovascular mortality in middle aged and elderly patients.

PubMed

Butnoriene, Jurate; Bunevicius, Adomas; Saudargiene, Ausra; Nemeroff, Charles B; Norkus, Antanas; Ciceniene, Vile; Bunevicius, Robertas

2015-01-01

Studies investigating specifically whether metabolic syndrome (MetS) and common psychiatric disorders are independently associated with mortality are lacking. In a middle-aged general population, we investigated the association of the MetS, current major depressive episode (MDE), lifetime MDE, and generalized anxiety disorder (GAD) with ten-year all-cause and cardiovascular disease mortality. From February 2003 until January 2004, 1115 individuals aged 45 years and older were randomly selected from a primary care practice and prospectively evaluated for: (1) MetS (The World Health Organization [WHO], National Cholesterol Education Program/Adult Treatment Panel III and International Diabetes Federation [IDF] definitions); (2) current MDE and GAD, and lifetime MDE (Mini International Neuropsychiatric Interview); and (3) conventional cardiovascular risk factors. Follow-up continued through January, 2013. During the 9.32 ± 0.47 years of follow-up, there were 248 deaths, of which 148 deaths were attributed to cardiovascular causes. In women, WHO-MetS and IDF-MetS were associated with greater all-cause (HR-values range from 1.77 to 1.91; p-values ≤ 0.012) and cardiovascular (HR-values range from 1.83 to 2.77; p-values ≤ 0.013) mortality independent of cardiovascular risk factors and MDE/GAD. Current GAD predicted greater cardiovascular mortality (HR-values range from 1.86 to 1.99; p-values ≤ 0.025) independently from MetS and cardiovascular risk factors. In men, the MetS and MDE/GAD were not associated with mortality. In middle aged women, the MetS and GAD predicted greater 10-year cardiovascular mortality independently from each other; 10-year all-cause mortality was independently predicted by the MetS. MetS and GAD should be considered important and independent mortality risk factors in women. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Nonalcoholic fatty liver disease is an independent risk factor for atherosclerosis in young adult men.

PubMed

Ozturk, Kadir; Uygun, Ahmet; Guler, Ahmet Kerem; Demirci, Hakan; Ozdemir, Cafer; Cakir, Mehmet; Sakin, Yusuf Serdar; Turker, Turker; Sari, Sebahattin; Demirbas, Seref; Karslıoğlu, Yıldırım; Saglam, Mutlu

2015-06-01

The possible cause of accelerated atherosclerosis in NAFLD may be the relationship with the MetS and its components. Our primary goal was to evaluate the relationship between NAFLD and subclinical atherosclerosis in adult male patients between 20 and 40 years of age. Moreover, we aimed to investigate the changes in this association according to the presence or absence of MetS. Sixty-one male patients with biopsy-proven NAFLD and 41 healthy male volunteers were enrolled. In order to exclude any interference of confounding factors, we studied a specifically selected group with no additional cardiovascular risk. PWV, CIMT and FMD levels were measured in all patients and controls. The levels of cf-PWV were significantly higher in SS and NASH patients compared to the control group (P < 0.001); no significant difference was found between SS and NASH patients (P > 0.05). We found significantly decreased FMD levels in patients with SS and NASH compared with control subjects (P < 0.001). Subjects with NASH had significantly greater CIMT measurements than the SS and controls (P = 0.026, P < 0.001, respectively). Although, NAFLD patients with MetS had increased cf-PWV and CIMT and reduced FMD compared to healthy subjects (P < 0.05), no significant difference existed between NAFLD with Mets and NAFLD without MetS in terms of cf-PWV, CIMT and FMD (P > 0.05) CONCLUSION: The present study showed that the presence of NAFLD leads to increased risk of endothelial dysfunction and atherosclerosis in adult male patients, independent of MetS. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Sensitivity, Specificity, and Predictive Values of Pediatric Metabolic Syndrome Components in Relation to Adult Metabolic Syndrome: The Princeton LRC Follow-up Study

PubMed Central

Huang, Terry T-K; Nansel, Tonja R.; Belsheim, Allen R.; Morrison, John A.

2008-01-01

Objective To estimate the sensitivity, specificity, and predictive values of pediatric metabolic syndrome (MetS) components (obesity, fasting glucose, triglycerides, high-density lipoprotein, and blood pressure) at various cutoffs in relation to adult MetS. Study design Data from the NHLBI Lipid Research Clinics (LRC) Princeton Prevalence Study (1973–76) and the Princeton Follow-up Study (PFS, 2000-4) were used to calculate sensitivity, specificity, and positive and negative predictive values for each component at a given cutoff, as well as for aggregates of components. Results Individual pediatric components alone showed low to moderate sensitivity, high specificity, and moderate predictive values in relation to adult MetS. When all five pediatric MetS components were considered, the presence of at least one abnormality had higher sensitivity for adult MetS than individual components alone. When multiple abnormalities were mandatory for MetS, positive predictive value was high and sensitivity was low. Childhood body mass alone showed neither high sensitivity nor high positive predictive value for adult MetS. Conclusions Considering multiple metabolic variables in childhood can improve the predictive utility for adult MetS, compared to each component or body mass alone. MetS variables may be useful for identifying some at risk children for prevention interventions. PMID:18206687

Association of the Catechol-O-Methyltransferase (COMT) Val158Met Polymorphism and Anxiety-Related Traits: A Meta-Analysis

PubMed Central

Lee, Lewina O.; Prescott, Carol A.

2014-01-01

Objectives The main goals of this study were: (i) to examine genotypic association of the COMT val158met polymorphism with anxiety-related traits via a meta-analysis; (ii) to examine sex and ethnicity as moderators of the association, and (iii) to evaluate whether the association differed by particular anxiety traits. Methods Association studies of the COMT val18met polymorphism and anxiety traits were identified from the PubMed or PsycInfo databases, conference abstracts and listserv postings. Exclusion criteria were: (a) pediatric samples, (b) exclusively clinical samples, and (c) samples selected for a non-anxiety phenotype. Standardized mean differences in anxiety between genotypes were aggregated to produce mean effect sizes across all available samples, and for subgroups stratified by sex and ethnicity (Caucasians vs. Asians). Construct-specific analysis was conducted to evaluate the association of COMT with neuroticism, harm avoidance, and behavioral inhibition. Results Twenty seven eligible studies (N=15,979) with available data were identified. Overall findings indicate sex-specific and ethnic-specific effects: Val homozygotes had higher neuroticism than Met homozygotes in studies of Caucasian males ( ES¯=0.13, 95%CI: 0.02 – 0.25, p = 0.03), and higher harm avoidance in studies of Asian males ( ES¯=0.43, 95%CI: 0.14 – 0.72, p = 0.004). No significant associations were found in women and effect sizes were diminished when studies were aggregated across ethnicity or anxiety traits. Conclusions: This meta-analysis provides evidence for sex and ethnicity differences in the association of the COMT val158met polymorphism with anxiety traits. Our findings contribute to current knowledge on the relation between prefrontal dopaminergic transmission and anxiety. PMID:24300663

Optimal cutoff points for HOMA-IR and QUICKI in the diagnosis of metabolic syndrome and non-alcoholic fatty liver disease: A population based study.

PubMed

Motamed, Nima; Miresmail, Seyed Javad Haji; Rabiee, Behnam; Keyvani, Hossein; Farahani, Behzad; Maadi, Mansooreh; Zamani, Farhad

2016-03-01

The present study was carried out to determine the optimal cutoff points for homeostatic model assessment (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) in the diagnosis of metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD). The baseline data of 5511 subjects aged ≥18years of a cohort study in northern Iran were utilized to analyze. Receiver operating characteristic (ROC) analysis was conducted to determine the discriminatory capability of HOMA-IR and QUICKI in the diagnosis of MetS and NAFLD. Youden index was utilized to determine the optimal cutoff points of HOMA-IR and QUICKI in the diagnosis of MetS and NAFLD. The optimal cutoff points for HOMA-IR in the diagnosis of MetS and NAFLD were 2.0 [sensitivity=64.4%, specificity=66.8%] and 1.79 [sensitivity=66.2%, specificity=62.2%] in men and were 2.5 [sensitivity=57.6%, specificity=67.9%] and 1.95 [sensitivity=65.1%, specificity=54.7%] in women respectively. Furthermore, the optimal cutoff points for QUICKI in the diagnosis of MetS and NAFLD were 0.343 [sensitivity=63.7%, specificity=67.8%] and 0.347 [sensitivity=62.9%, specificity=65.0%] in men and were 0.331 [sensitivity=55.7%, specificity=70.7%] and 0.333 [sensitivity=53.2%, specificity=67.7%] in women respectively. Not only the optimal cutoff points of HOMA-IR and QUICKI were different for MetS and NAFLD, but also different cutoff points were obtained for men and women for each of these two conditions. Copyright © 2016 Elsevier Inc. All rights reserved.

Association of plasma aldosterone with the metabolic syndrome in two German populations.

PubMed

Hannemann, Anke; Meisinger, Christa; Bidlingmaier, Martin; Döring, Angela; Thorand, Barbara; Heier, Margit; Belcredi, Petra; Ladwig, Karl-Heinz; Wallaschofski, Henri; Friedrich, Nele; Schipf, Sabine; Lüdemann, Jan; Rettig, Rainer; Peters, Jörg; Völzke, Henry; Seissler, Jochen; Beuschlein, Felix; Nauck, Matthias; Reincke, Martin

2011-05-01

The aim of this study was to analyze the potential association of the plasma aldosterone concentration (PAC) with the metabolic syndrome (MetS) and its components in two German population-based studies. We selected 2830 and 2901 participants (31-80 years) from the follow-ups of the Study of Health in Pomerania (SHIP)-1 and the Cooperative Health Research in the Region of Augsburg (KORA) F4 respectively. MetS was defined as the presence of at least three out of the following five criteria: waist circumference ≥94 cm (men (m)) and ≥80 cm (women (w)); high-density lipoprotein (HDL) cholesterol <1.0 mmol/l (m) and <1.3 mmol/l (w); blood pressure ≥130/85 mmHg or antihypertensive treatment; non-fasting glucose (SHIP-1) ≥8 mmol/l, fasting glucose (KORA F4) ≥5.55 mmol/l or antidiabetic treatment; non-fasting triglycerides (SHIP-1) ≥2.3 mmol/l, fasting triglycerides (KORA F4) ≥1.7 mmol/l, or lipid-lowering treatment. We calculated logistic regression models by comparing the highest study- and sex-specific PAC quintiles versus all lower quintiles. MetS was common with 48.1% (m) and 34.8% (w) in SHIP-1 and 42.7% (m) and 27.5% (w) in KORA F4. Our logistic regression models revealed associations of PAC with MetS, elevated triglycerides, and decreased HDL cholesterol in SHIP-1 and KORA F4. Our findings add to the increasing evidence supporting a relation between aldosterone and MetS and suggest that aldosterone may be involved in the pathophysiology of MetS and lipid metabolism disorders.

The Link of Self-Reported Insomnia Symptoms and Sleep Duration with Metabolic Syndrome: A Chinese Population-Based Study.

PubMed

Lin, Shih-Chieh; Sun, Chien-An; You, San-Lin; Hwang, Lee-Ching; Liang, Chun-Yu; Yang, Tsan; Bai, Chyi-Huey; Chen, Chien-Hua; Wei, Cheng-Yu; Chou, Yu-Ching

2016-06-01

The aims of this study are to investigate the relationships of metabolic syndrome (MetS) with insomnia symptoms and sleep duration in a Chinese adult population. Data from a nationwide epidemiological survey conducted on residents from randomly selected districts in Taiwan in 2007 were used for this cross-sectional population-based study. A total of 4,197 participants were included in this study. Insomnia symptoms, including difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), early morning awakening (EMA), were assessed using the Insomnia Self-Assessment Inventory questionnaire. Subjects were divided into 3 groups based upon their reported sleep duration (< 7, 7-8, and ≥ 9 h per night). Odds ratios (ORs) and 95% confidence intervals (CIs) derived from multivariable logistic regression were used to evaluate the study aims. The endorsement of DIS and DMS were cross-sectionally associated with the MetS after adjustment for sleep duration (OR [95% CI] was 1.24 [1.01-1.51] and 1.28 [1.02-1.61], respectively). In addition, short sleep duration was significantly associated with the prevalence of MetS independent of insomnia symptoms (OR [95% CI] was 1.54 [1.05-2.47]). However, there was no significant combined effect of insomnia symptoms and sleep duration on the prevalence of MetS. The current investigation shows that short sleep duration and insomnia symptoms, specifically DIS and DMS, were significant correlates of MetS. These findings should be replicated in prospective studies using both sleep duration and sleep quality measures. © 2016 Associated Professional Sleep Societies, LLC.

Association of brain-derived neurotrophic factor valine to methionine polymorphism with sexual dysfunction following selective serotonin reuptake inhibitor treatment in female patients with major depressive disorder.

PubMed

Nazree, Nur Elia; Mohamed, Zahurin; Reynolds, Gavin P; Mohd Zain, Shamsul; Masiran, Ruziana; Sidi, Hatta; Chong, Lu Ann; Hway, Anne Yee; Adlan, Aida Syarinaz; Zainal, Nor Zuraida

2016-12-01

The occurrence of female sexual dysfunction (FSD) in patients with major depressive disorder (MDD) receiving selective serotonin reuptake inhibitors (SSRIs) treatment gives negative impacts on patients' quality of life and causes treatment discontinuation. We aimed to investigate whether genetic polymorphism of identified candidate gene is associated with FSD in our study population. This is a cross-sectional study. A total of 95 female patients with MDD who met the criteria of the study were recruited and were specifically assessed on the sexual function by trained psychiatrists. Patients' DNA was genotyped for BDNF Val66Met polymorphism using real-time polymerase chain reaction. The prevalence of FSD in this study is 31.6%. In the FSD group, patients with problematic marriage were significantly more frequent compared with patients who did not have problematic marriage (P = 0.009). Significant association was detected in the lubrication domain with BDNF Val66Met polymorphism (P = 0.030) using additive genetic model, with even stronger association when using the recessive model (P = 0.013). This study suggested that there was no significant association between BDNF Val66Met with FSD. However, this polymorphism is significantly associated with lubrication disorder in patients treated with SSRIs. © 2015 Wiley Publishing Asia Pty Ltd.

Design and optimization of a series of 1-sulfonylpyrazolo[4,3-b]pyridines as selective c-Met inhibitors.

PubMed

Ma, Yuchi; Sun, Guangqiang; Chen, Danqi; Peng, Xia; Chen, Yue-Lei; Su, Yi; Ji, Yinchun; Liang, Jin; Wang, Xin; Chen, Lin; Ding, Jian; Xiong, Bing; Ai, Jing; Geng, Meiyu; Shen, Jingkang

2015-03-12

c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit 7. By rational design, a novel sulfonylpyrazolo[4,3-b]pyridine 9 with improved DMPK properties was discovered. Further elaboration of π-π stacking interactions and solvent accessible polar moieties led to a series of highly potent and selective type I c-Met inhibitors. On the basis of in vitro and in vivo pharmacological and pharmacokinetics studies, compound 46 was selected as a preclinical candidate for further anticancer drug development.

Advances in Bacterial Methionine Aminopeptidase Inhibition

PubMed Central

Helgren, Travis R.; Wangtrakuldee, Phumvadee; Staker, Bart L.; Hagen, Timothy J.

2016-01-01

Methionine aminopeptidases (MetAPs) are metalloenzymes that cleave the N-terminal methionine from newly synthesized peptides and proteins. These MetAP enzymes are present in bacteria, and knockout experiments have shown that MetAP activity is essential for cell life, suggesting that MetAPs are good antibacterial drug targets. MetAP enzymes are also present in the human host and selectivity is essential. There have been significant structural biology efforts and over 65 protein crystal structures of bacterial MetAPs are deposited into the PDB. This review highlights the available crystallographic data for bacterial MetAPs. Structural comparison of bacterial MetAPs with human MetAPs highlights differences that can lead to selectivity. In addition, this review includes the chemical diversity of molecules that bind and inhibit the bacterial MetAP enzymes. Analysis of the structural biology and chemical space of known bacterial MetAP inhibitors leads to a greater understanding of this antibacterial target and the likely development of potential antibacterial agents. PMID:26268344

Formation of met-cars and face-centered cubic structures. Thermodynamically or kinetically controlled

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wei, S.; Guo, B.C.; Deng, H.T.

1994-05-18

On the basis of a series of experimental studies from our laboratory, it is well established that metallocarbohedrenes, or Met-Cars for short, are a stable class of cluster materials. To account for their exceptional stability, we initially proposed a pentagonal dodecahedron structure. This cage-like structure is consistent with all the experimental findings. In general, there are two possible structures that can be developed in these metal-carbon systems, i.e., Met-Cars and cubes. Since only one structural pattern is generally observed for one particular cluster system, it has been suggested that their thermodynamical stabilities might be responsible for the selective formation ofmore » specific structures, e.g., Met-Cars or fcc structures. Herein, we present new experimental results on the system of Nb[sub m]C[sub n] under various conditions. It is shown that the experimental conditions are extremely critical for the formation of either Met-Cars or cubic structures, as predicted by Reddy and Khanma. Moreover, the new data show that the cubic structures do not develop on top of Met-Cars, but rather, they grow independently. The experiments were performed by using both time-of-flight and quadrupole mass spectrometer techniques coupled with a laser vaporization source. 23 refs., 1 fig.« less

Design, synthesis, and evaluation of (2S,4R)-Ketoconazole sulfonamide analogs as potential treatments for Metabolic Syndrome.

PubMed

Blass, Benjamin E; Iyer, Pravin; Abou-Gharbia, Magid; Childers, Wayne E; Gordon, John C; Ramanjulu, Mercy; Morton, George; Arumugam, Premkumar; Boruwa, Joshodeep; Ellingboe, John; Mitra, Sayan; Nimmareddy, Rajashekar Reddy; Paliwal, Shalini; Rajasekhar, Jamallamudi; Shivakumar, Savithiri; Srivastava, Pratima; Tangirala, Raghuram S; Venkataramanaiah, Konda; Yanamandra, Mahesh

2016-12-01

Metabolic Syndrome, also referred to as 'Syndrome X' or 'Insulin Resistance Syndrome,' remains a major, unmet medical need despite over 30years of intense effort. Recent research suggests that there may be a causal link between this condition and abnormal glucocorticoid processing. Specifically, dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis leads to increased systemic cortisol concentrations. Cushing' syndrome, a disorder that is also typified by a marked elevation in levels of cortisol, produces clinical symptomology that is similar to those observed in MetS, and they can be alleviated by decreasing circulating cortisol concentrations. As a result, it has been suggested that decreasing systemic cortisol concentration might have a positive impact on the progression of MetS. This could be accomplished through inhibition of enzymes in the cortisol synthetic pathway, 11β-hydroxylase (Cyp11B1), 17α-hydroxylase-C17,20-lyase (Cyp17), and 21-hydroxylase (Cyp21). We have identified a series of novel sulfonamide analogs of (2S,4R)-Ketoconazole that are potent inhibitors of these enzymes. In addition, selected members of this class of compounds have pharmacokinetic properties consistent with orally delivered drugs, making them well suited to further investigation as potential therapies for MetS. Copyright © 2016 Elsevier Ltd. All rights reserved.

The BDNF Val66Met polymorphism impairs synaptic transmission and plasticity in the infralimbic medial prefrontal cortex

PubMed Central

Pattwell, Siobhan S.; Bath, Kevin G.; Perez-Castro, Rosalia; Lee, Francis S.; Chao, Moses V.; Ninan, Ipe

2012-01-01

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is a common human single nucleotide polymorphism (SNP) that affects the regulated release of BDNF, and has been implicated in affective disorders and cognitive dysfunction. A decreased activation of the infralimbic medial prefrontal cortex (IL-mPFC), a brain region critical for the regulation of affective behaviors, has been described in BDNFMet carriers. However, it is unclear whether and how the Val66Met polymorphism affects the IL-mPFC synapses. Here we report that spike timing-dependent plasticity (STDP) was absent in the IL-mPFC pyramidal neurons from BDNFMet/Met mice, a mouse that recapitulates the specific phenotypic properties of the human BDNF Val66Met polymorphism. Also, we observed a decrease in N-methyl-D-aspartic acid (NMDA) and γ-aminobutyric acid (GABA) receptor-mediated synaptic transmission in the pyramidal neurons of BDNFMet/Met mice. While BDNF enhanced non-NMDA receptor transmission and depressed GABA receptor transmission in the wild-type mice, both effects were absent in BDNFMet/Met mice after BDNF treatment. Indeed, exogenous BDNF reversed the deficits in STDP and NMDA receptor transmission in BDNFMet/Met neurons. BDNF-mediated selective reversal of the deficit in plasticity and NMDA receptor transmission, but its lack of effect on GABA and non-NMDA receptor transmission in BDNFMet/Met mice, suggests separate mechanisms of Val66Met polymorphism upon synaptic transmission. The effect of the Val66Met polymorphism on synaptic transmission and plasticity in the IL-mPFC represents a mechanism to account for this SNP's impact on affective disorders and cognitive dysfunction. PMID:22396415

HIV Drug Resistance Early Warning Indicators in Namibia for Public Health Action

PubMed Central

Jonas, Anna; Gweshe, Justice; Siboleka, Milner; DeKlerk, Michael; Gawanab, Michael; Badi, Alfons; Sumbi, Victor; Pereko, Dawn; Blom, Abraham; Mwinga, Samson; Jordan, Michael R.; Jerger, Logan; Lau, Kiger; Hong, Steven Y.

2013-01-01

Background HIV drug resistance (HIVDR) testing is not routinely available in many resource-limited settings, therefore antiretroviral therapy (ART) program and site factors known to be associated with emergence of HIVDR should be monitored to optimize the quality of patient care and minimize the emergence of preventable HIVDR. Methods In 2010, Namibia selected five World Health Organization Early Warning Indicators (EWIs) and scaled-up monitoring from 9 to 33 ART sites: ART prescribing practices, Patients lost to follow-up (LTFU) at 12 months, Patients switched to a second-line regimen at 12 months, On-time antiretroviral (ARV) drug pick-up, and ARV drug-supply continuity. Results Records allowed reporting on three of the five selected EWIs. 22 of 33 (67%) sites met the target of 100% initiated on appropriate first-line regimens. 17 of 33 (52%) sites met the target of ≤20% LTFU. 15 of 33 (45%) sites met the target of 0% switched to a second-line regimen. Conclusions EWI monitoring directly resulted in public health action which will optimize the quality of care, specifically the strengthening of ART record systems, engagement of ART sites, and operational research for improved adherence assessment and ART patient defaulter tracing. PMID:23762406

Low sensitivity of the metabolic syndrome to identify adolescents with impaired glucose tolerance: an analysis of NHANES 1999-2010.

PubMed

DeBoer, Mark D; Gurka, Matthew J

2014-04-23

The presence of impaired glucose tolerance (IGT) and metabolic syndrome (MetS) are two risk factors for Type 2 diabetes. The inter-relatedness of these factors among adolescents is unclear. We evaluated the sensitivity and specificity of MetS for identifying IGT in an unselected group of adolescents undergoing oral glucose tolerance tests (OGTT) in the National Health and Nutrition Evaluation Survey 1999-2010. We characterized IGT as a 2-hour glucose ≥140 mg/dL and MetS using ATP-III-based criteria and a continuous sex- and race/ethnicity-specific MetS Z-score at cut-offs of +1.0 and +0.75 standard deviations (SD) above the mean. Among 1513 adolescents, IGT was present in 4.8%, while ATP-III-MetS was present in 7.9%. MetS performed poorly in identifying adolescents with IGT with a sensitivity/specificity of 23.7%/92.9% for ATP-III-MetS, 23.6%/90.8% for the MetS Z-score at +1.0 SD and 35.8%/85.0 for the MetS Z-score at +0.75 SD. Sensitivity was higher (and specificity lower) but was still overall poor among overweight/obese adolescents: 44.7%/83.0% for ATP-III-MetS, 43.1%/77.1% for the MetS Z-score at +1.0 SD and 64.3%/64.3% for MetS Z-score at +0.75 SD. This lack of overlap between MetS and IGT may indicate that assessment of MetS is not likely to be a good indicator of which adolescents to screen using OGTT. These data further underscore the importance of other potential contributors to IGT, including Type 1 diabetes and genetic causes of poor beta-cell function. Practitioners should keep these potential causes of IGT in mind, even when evaluating obese adolescents with IGT.

A genetically encoded and gate for cell-targeted metabolic labeling of proteins.

PubMed

Mahdavi, Alborz; Segall-Shapiro, Thomas H; Kou, Songzi; Jindal, Granton A; Hoff, Kevin G; Liu, Shirley; Chitsaz, Mohsen; Ismagilov, Rustem F; Silberg, Jonathan J; Tirrell, David A

2013-02-27

We describe a genetic AND gate for cell-targeted metabolic labeling and proteomic analysis in complex cellular systems. The centerpiece of the AND gate is a bisected methionyl-tRNA synthetase (MetRS) that charges the Met surrogate azidonorleucine (Anl) to tRNA(Met). Cellular protein labeling occurs only upon activation of two different promoters that drive expression of the N- and C-terminal fragments of the bisected MetRS. Anl-labeled proteins can be tagged with fluorescent dyes or affinity reagents via either copper-catalyzed or strain-promoted azide-alkyne cycloaddition. Protein labeling is apparent within 5 min after addition of Anl to bacterial cells in which the AND gate has been activated. This method allows spatial and temporal control of proteomic labeling and identification of proteins made in specific cellular subpopulations. The approach is demonstrated by selective labeling of proteins in bacterial cells immobilized in the center of a laminar-flow microfluidic channel, where they are exposed to overlapping, opposed gradients of inducers of the N- and C-terminal MetRS fragments. The observed labeling profile is predicted accurately from the strengths of the individual input signals.

MET inhibition overcomes radiation resistance of glioblastoma stem-like cells.

PubMed

De Bacco, Francesca; D'Ambrosio, Antonio; Casanova, Elena; Orzan, Francesca; Neggia, Roberta; Albano, Raffaella; Verginelli, Federica; Cominelli, Manuela; Poliani, Pietro L; Luraghi, Paolo; Reato, Gigliola; Pellegatta, Serena; Finocchiaro, Gaetano; Perera, Timothy; Garibaldi, Elisabetta; Gabriele, Pietro; Comoglio, Paolo M; Boccaccio, Carla

2016-05-01

Glioblastoma (GBM) contains stem-like cells (GSCs) known to be resistant to ionizing radiation and thus responsible for therapeutic failure and rapidly lethal tumor recurrence. It is known that GSC radioresistance relies on efficient activation of the DNA damage response, but the mechanisms linking this response with the stem status are still unclear. Here, we show that the MET receptor kinase, a functional marker of GSCs, is specifically expressed in a subset of radioresistant GSCs and overexpressed in human GBM recurring after radiotherapy. We elucidate that MET promotes GSC radioresistance through a novel mechanism, relying on AKT activity and leading to (i) sustained activation of Aurora kinase A, ATM kinase, and the downstream effectors of DNA repair, and (ii) phosphorylation and cytoplasmic retention of p21, which is associated with anti-apoptotic functions. We show that MET pharmacological inhibition causes DNA damage accumulation in irradiated GSCs and their depletion in vitro and in GBMs generated by GSC xenotransplantation. Preclinical evidence is thus provided that MET inhibitors can radiosensitize tumors and convert GSC-positive selection, induced by radiotherapy, into GSC eradication. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

eIF1 Loop 2 interactions with Met-tRNAi control the accuracy of start codon selection by the scanning preinitiation complex.

PubMed

Thakur, Anil; Hinnebusch, Alan G

2018-05-01

The eukaryotic 43S preinitiation complex (PIC), bearing initiator methionyl transfer RNA (Met-tRNA i ) in a ternary complex (TC) with eukaryotic initiation factor 2 (eIF2)-GTP, scans the mRNA leader for an AUG codon in favorable context. AUG recognition evokes rearrangement from an open PIC conformation with TC in a "P OUT " state to a closed conformation with TC more tightly bound in a "P IN " state. eIF1 binds to the 40S subunit and exerts a dual role of enhancing TC binding to the open PIC conformation while antagonizing the P IN state, necessitating eIF1 dissociation for start codon selection. Structures of reconstituted PICs reveal juxtaposition of eIF1 Loop 2 with the Met-tRNA i D loop in the P IN state and predict a distortion of Loop 2 from its conformation in the open complex to avoid a clash with Met-tRNA i We show that Ala substitutions in Loop 2 increase initiation at both near-cognate UUG codons and AUG codons in poor context. Consistently, the D71A-M74A double substitution stabilizes TC binding to 48S PICs reconstituted with mRNA harboring a UUG start codon, without affecting eIF1 affinity for 40S subunits. Relatively stronger effects were conferred by arginine substitutions; and no Loop 2 substitutions perturbed the rate of TC loading on scanning 40S subunits in vivo. Thus, Loop 2-D loop interactions specifically impede Met-tRNA i accommodation in the P IN state without influencing the P OUT mode of TC binding; and Arg substitutions convert the Loop 2-tRNA i clash to an electrostatic attraction that stabilizes P IN and enhances selection of poor start codons in vivo.

Selective bispecific T cell recruiting antibody and antitumor activity of adoptive T cell transfer.

PubMed

Kobold, Sebastian; Steffen, Julius; Chaloupka, Michael; Grassmann, Simon; Henkel, Jonas; Castoldi, Raffaella; Zeng, Yi; Chmielewski, Markus; Schmollinger, Jan C; Schnurr, Max; Rothenfußer, Simon; Schendel, Dolores J; Abken, Hinrich; Sustmann, Claudio; Niederfellner, Gerhard; Klein, Christian; Bourquin, Carole; Endres, Stefan

2015-01-01

One bottleneck for adoptive T cell therapy (ACT) is recruitment of T cells into tumors. We hypothesized that combining tumor-specific T cells, modified with a marker antigen and a bispecific antibody (BiAb) that selectively recognizes transduced T cells and tumor cells would improve T cell recruitment to tumors and enhance therapeutic efficacy. SV40 T antigen-specific T cells from T cell receptor (TCR)-I-transgenic mice were transduced with a truncated human epidermal growth factor receptor (EGFR) as a marker protein. Targeting and killing by combined ACT and anti-EGFR-anti-EpCAM BiAb therapy was analyzed in C57Bl/6 mice (n = six to 12 per group) carrying subcutaneous tumors of the murine gastric cancer cell line GC8 (SV40(+) and EpCAM(+)). Anti-EGFR x anti-c-Met BiAb was used for targeting of human tumor-specific T cells to c-Met(+) human tumor cell lines. Differences between experimental conditions were analyzed using the Student's t test, and differences in tumor growth with two-way analysis of variance. Overall survival was analyzed by log-rank test. All statistical tests were two-sided. The BiAb linked EGFR-transduced T cells to tumor cells and enhanced tumor cell lysis. In vivo, the combination of ACT and Biab produced increased T cell infiltration of tumors, retarded tumor growth, and prolonged survival compared with ACT with a control antibody (median survival 95 vs 75 days, P < .001). In human cells, this strategy enhanced recruitment of human EGFR-transduced T cells to immobilized c-Met and recognition of tyrosinase(+) melanoma cells by TCR-, as well as of CEA(+) colon cancer cells by chimeric antigen receptor (CAR)-modified T cells. BiAb recruitment of tumor-specific T cells transduced with a marker antigen to tumor cells may enhance efficacy of ACT. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Validation of periodontitis screening model using sociodemographic, systemic, and molecular information in a Korean population.

PubMed

Kim, Hyun-Duck; Sukhbaatar, Munkhzaya; Shin, Myungseop; Ahn, Yoo-Been; Yoo, Wook-Sung

2014-12-01

This study aims to evaluate and validate a periodontitis screening model that includes sociodemographic, metabolic syndrome (MetS), and molecular information, including gingival crevicular fluid (GCF), matrix metalloproteinase (MMP), and blood cytokines. The authors selected 506 participants from the Shiwha-Banwol cohort: 322 participants from the 2005 cohort for deriving the screening model and 184 participants from the 2007 cohort for its validation. Periodontitis was assessed by dentists using the community periodontal index. Interleukin (IL)-6, IL-8, and tumor necrosis factor-α in blood and MMP-8, -9, and -13 in GCF were assayed using enzyme-linked immunosorbent assay. MetS was assessed by physicians using physical examination and blood laboratory data. Information about age, sex, income, smoking, and drinking was obtained by interview. Logistic regression analysis was applied to finalize the best-fitting model and validate the model using sensitivity, specificity, and c-statistics. The derived model for periodontitis screening had a sensitivity of 0.73, specificity of 0.85, and c-statistic of 0.86 (P <0.001); those of the validated model were 0.64, 0.91, and 0.83 (P <0.001), respectively. The model that included age, sex, income, smoking, drinking, and blood and GCF biomarkers could be useful in screening for periodontitis. A future prospective study is indicated for evaluating this model's ability to predict the occurrence of periodontitis.

Regular Tooth Brushing is Associated with a Decreased Risk of Metabolic Syndrome According to a Medical Check-Up Database.

PubMed

Tsutsumi, Chiyo; Kakuma, Tatsuyuki

2015-01-01

Associations have been reported between periodontal disease and increased cardiovascular disease risk, as well as between healthy self-reported tooth brushing behavior and reduced cardiovascular disease risk. We examined the association between self-reported tooth brushing behavior and the risk of metabolic syndrome (MetS) using a large medical check-up database. A total of 12,548 medical checkup records from a medical screening center in a city in southwest Japan were assessed. Subjects were aged 30 to 59 years. As lifestyle is associated with both tooth brushing and MetS, many lifestyle variables were considered as potential confounders. Logistic regression model were employed with a list of 127 lifestyle variables. Twenty variables associated with both tooth brushing and MetS were selected for both males and females. Furthermore, final confounding variables were selected by principal component analysis to avoid collinearity problems. The association of tooth brushing and MetS was evaluated for males and females separately by calculating adjusted odds ratios (ORs) with selected confounders plus age. The association between daily tooth brushing frequency and MetS risk for both genders was significant after adjusting for confounders, with the risk of MetS decreasing with increased frequency of daily tooth brushing (adjusted OR = 0.57 (95%Cl:0.48-0.81), 0.50 (95%Cl:0.35-0.71), 0.42 (95%Cl: 0.29-0.61) for males and adjusted OR = 0.65 (95%Cl:0.48-0.87), 0.44 (95%Cl:0.32-0.62) for females). Therefore, oral hygiene, including the frequency of tooth brushing as a significant component, may be an important factor in preventing MetS.

Activated MET acts as a salvage signal after treatment with alectinib, a selective ALK inhibitor, in ALK-positive non-small cell lung cancer.

PubMed

Kogita, Akihiro; Togashi, Yosuke; Hayashi, Hidetoshi; Banno, Eri; Terashima, Masato; De Velasco, Marco A; Sakai, Kazuko; Fujita, Yoshihiko; Tomida, Shuta; Takeyama, Yoshifumi; Okuno, Kiyotaka; Nakagawa, Kazuhiko; Nishio, Kazuto

2015-03-01

Non-small cell lung cancer (NSCLC) carrying echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements is hypersensitive to ALK inhibitors, including crizotinib and alectinib. Crizotinib was initially designed as a MET inhibitor, whereas alectinib is a selective ALK inhibitor. The MET signal, which is inhibited by crizotinib but not by alectinib, is dysregulated in many human cancers. However, the role of the MET signal in ALK-positive NSCLC remains unclear. In this study, we found that hepatocyte growth factor (HGF), ligand of MET, mediated the resistance to alectinib, but not to crizotinib, via the MET signal in ALK-positive NSCLC cell lines (H3122 and H2228 cell lines). In addition, alectinib activated the MET signal even in the absence of HGF and the inhibition of the MET signal enhanced the efficacy of alectinib. These findings suggest that activated MET acts as a salvage signal in ALK-positive NSCLC. This novel role of the MET signal in ALK-positive NSCLC may pave the way for further clinical trials examining MET inhibitors.

Energy Cost of Lower Body Dressing, Pop-Over Transfers, and Manual Wheelchair Propulsion in People with Paraplegia Due to Motor-Complete Spinal Cord Injury

PubMed Central

McCormick, Zachary; Liem, Brian; Jacobs, Geneva; Hwang, Peter; Hornby, Thomas George; Rydberg, Leslie; Roth, Elliot J.

2015-01-01

Background: Energy required for able-bodied individuals to perform common activities is well documented, whereas energy associated with daily activities among people with spinal cord injury (SCI) is less understood. Objective: To determine energy expended during several basic physical tasks specific to individuals with paraplegia due to motor-complete SCI. Methods: Sixteen adults with motor-complete SCI below T2 level and duration of paraplegia greater than 3 months were included. Oxygen consumption (VO2), caloric expenditure, and heart rate were measured at rest and while participants performed lower body dressing (LBD), pop-over transfers (POTs), and manual wheelchair propulsion (MWP) at a self-selected pace. These data were used to calculate energy expenditure in standard metabolic equivalents (METs), as defined by 1 MET = 3.5 mL O2/kg/min, and in SCI METs using the conversion 1 SCI MET = 2.7 mL O2/kg/min. Results: VO2 at rest was 3.0 ± 0.9 mL O2/kg/min, which equated to 0.9 ± 0.3 standard METs and 1.1 ± 0.4 SCI METs in energy expenditure. LBD required 3.2 ± 0.7 METs and 4.1 ± 0.9 SCI METs; POTs required 3.4 ± 1.0 METs and 4.5 ± 1.3 SCI METs; and MWP required 2.4 ± 0.6 METs and 3.1 ± 0.7 SCI METs. Conclusion: Resting VO2 for adults with motor-complete paraplegia is 3.0 mL O2/kg/min, which is lower than standard resting VO2 in able-bodied individuals. Progressively more energy is required to perform MWP, LBD, and POTs, respectively. Use of the standard METs formula may underestimate the level of intensity an individual with SCI uses to perform physical activities. PMID:26364283

Optimal cut-off of homeostasis model assessment of insulin resistance (HOMA-IR) for the diagnosis of metabolic syndrome: third national surveillance of risk factors of non-communicable diseases in Iran (SuRFNCD-2007).

PubMed

Esteghamati, Alireza; Ashraf, Haleh; Khalilzadeh, Omid; Zandieh, Ali; Nakhjavani, Manouchehr; Rashidi, Armin; Haghazali, Mehrdad; Asgari, Fereshteh

2010-04-07

We have recently determined the optimal cut-off of the homeostatic model assessment of insulin resistance for the diagnosis of insulin resistance (IR) and metabolic syndrome (MetS) in non-diabetic residents of Tehran, the capital of Iran. The aim of the present study is to establish the optimal cut-off at the national level in the Iranian population with and without diabetes. Data of the third National Surveillance of Risk Factors of Non-Communicable Diseases, available for 3,071 adult Iranian individuals aging 25-64 years were analyzed. MetS was defined according to the Adult Treatment Panel III (ATPIII) and International Diabetes Federation (IDF) criteria. HOMA-IR cut-offs from the 50th to the 95th percentile were calculated and sensitivity, specificity, and positive likelihood ratio for MetS diagnosis were determined. The receiver operating characteristic (ROC) curves of HOMA-IR for MetS diagnosis were depicted, and the optimal cut-offs were determined by two different methods: Youden index, and the shortest distance from the top left corner of the curve. The area under the curve (AUC) (95%CI) was 0.650 (0.631-0.670) for IDF-defined MetS and 0.683 (0.664-0.703) with the ATPIII definition. The optimal HOMA-IR cut-off for the diagnosis of IDF- and ATPIII-defined MetS in non-diabetic individuals was 1.775 (sensitivity: 57.3%, specificity: 65.3%, with ATPIII; sensitivity: 55.9%, specificity: 64.7%, with IDF). The optimal cut-offs in diabetic individuals were 3.875 (sensitivity: 49.7%, specificity: 69.6%) and 4.325 (sensitivity: 45.4%, specificity: 69.0%) for ATPIII- and IDF-defined MetS, respectively. We determined the optimal HOMA-IR cut-off points for the diagnosis of MetS in the Iranian population with and without diabetes.

Non-sedentary Lifestyle Can Reduce Hip Fracture Risk among Older Caucasians Adults: The Adventist Health Study-2.

PubMed

Lousuebsakul-Matthews, Vichuda; Thorpe, Donna; Knutsen, Raymond; Beeson, W Larry; Fraser, Gary E; Knutsen, Synnove F

2015-01-01

The beneficial effect of physical activity on reducing hip fracture risk has been supported in many previous studies. The present cohort study explores the relationship between total daily physical activity expressed as MET-hour/day and hip fracture risk among men over 50 years of age and postmenopausal women (n=22,836). Associations between self-reported hip fracture incidence and total daily physical activity and selected lifestyle factors were assessed using Cox proportional hazard regression. In gender-specific multivariable models, total activity above average (≥ 51 MET-hours per day for men, ≥ 48 MET-hours per day for women) compared to those with sedentary lifestyle (< 40 MET-hours per day) reduced the risk of hip fracture by 60% among men (HR=0.40, 95%CI: 0.23-0.70) (Ptrend=0.002) and 48% among women (HR=0.52, 95%CI: 0.32-0.84) (Ptrend=0.01). Our findings suggest that a moderate level of physical activity and avoiding a sedentary lifestyle can reduce the risk of hip fracture among the elderly.

Flammability Parameters of Candles

NASA Astrophysics Data System (ADS)

Balog, Karol; Kobetičová, Hana; Štefko, Tomáš

2017-06-01

The paper deals with the assessment of selected fire safety characteristics of candles. Weight loss of a candle during the burning process, candle burning rate, soot index, heat release rate and yield of carbon oxides were determined. Soot index was determined according to EN 15426: 2007 - Candles - Specification for Sooting Behavior. All samples met the prescribed amount of produced soot. Weight loss, heat release rate and the yield of carbon oxides were determined for one selected sample. While yield of CO increased during the measurement, the yield of CO2 decreased by half in 40 minutes.

Determining the profiles and parameters for gene amplification testing of growth factor receptors in lung cancer.

PubMed

Pros, Eva; Lantuejoul, Sylvie; Sanchez-Verde, Lydia; Castillo, Sandra D; Bonastre, Ester; Suarez-Gauthier, Ana; Conde, Esther; Cigudosa, Juan C; Lopez-Rios, Fernando; Torres-Lanzas, Juan; Castellví, Josep; Ramon y Cajal, Santiago; Brambilla, Elisabeth; Sanchez-Cespedes, Montse

2013-08-15

Growth factor receptors (GFRs) are amenable to therapeutic intervention in cancer and it is important to select patients appropriately. One of the mechanisms for activation of GFRs is gene amplification (GA) but discrepancies arising from the difficulties associated with data interpretation and the lack of agreed parameters confound the comparison of results from different laboratories. Here, we attempt to establish appropriate conditions for standardization of the determination of GA in a panel of GFRs. A NSCLC tissue microarray panel containing 302 samples was screened for alterations at ALK, FGFR1, FGFR2, FGFR3, ERBB2, IGF1R, KIT, MET and PDGFRA by FISH, immunostaining and/or real-time quantitative RT-PCR. Strong amplification was found for FGFR1, ERBB2, KIT/PDFGRA and MET, with frequencies ranging from 1 to 6%. Thresholds for overexpression and GA were established. Strong immunostaining was found in most tumors with ERBB2, MET and KIT amplification, although some tumors underwent strong immunostaining in the absence of GA. KIT and PDFGRA were always coamplified, but only one tumor showed PDGFRA overexpression, indicating that KIT is the main target. Amplification of FGFR1 predominated in squamous cell carcinomas, although the association with overexpression was inconclusive. Interestingly, alterations at ALK, MET, EGFR, ERBB2 and KRAS correlated with augmented levels of phospho-S6 protein, suggesting activation of the mTOR pathway, which may prove useful to pre-select tumors for testing. Overall, here, we provide with parameters for the determination of GA at ERBB2, MET, KIT and PDGFRA which could be implemented in the clinic to stratify lung cancer patients for specific treatments. Copyright © 2013 UICC.

Longitudinal association of antidepressant medication use with metabolic syndrome: Results of a 9-year follow-up of the D.E.S.I.R. cohort study.

PubMed

Azevedo Da Silva, Marine; Balkau, Beverley; Roussel, Ronan; Tichet, Jean; Fumeron, Frédéric; Fagherazzi, Guy; Nabi, Hermann

2016-12-01

To examine longitudinal associations between antidepressant medication use and the metabolic syndrome (MetS). 5014 participants (49.8% were men) from the D.E.S.I.R. cohort study, aged 30-65 years at baseline in 1994-1996, were followed over 9 years at 3-yearly intervals (1997-1999, 2000-2002, and 2003-2005). Antidepressant use and MetS, defined by the National Cholesterol Education Program Adult Treatment Panel III criteria (NCEP-ATP III) and the American Heart Association and the National Heart, Lung and Blood Institute (AHA/NHLBI) criteria, were assessed concurrently at four medical examinations. In fully-adjusted longitudinal logistic regression analyses based on generalized estimating equations, antidepressant users had a 9% (p=0.011) and a 6% (p=0.036) greater annual increase in the odds of having the MetS defined by NCEP-ATP III and AHA/NHLBI criteria respectively. Sex-specific analyses showed that this association was confined to men only. When the different types of antidepressant were considered, men who used selective serotonin reuptake inhibitors (SSRIs), imipramine type antidepressants or "other" antidepressants had a 52% (p=0.028), 31% (p=0.011), and 16% (p=0.016) greater annual increase in the odds of having the MetS over time compared to non-users, respectively. These associations depended on the definition of the MetS. Our longitudinal data showed that antidepressant use was associated with an increased odds of having the MetS in men but not in women and this was mainly for SSRIs, imipramine type and "other" antidepressants. People on antidepressants may need to be checked regularly for the elements of the metabolic syndrome treatable by change in diet, physical activity and/or by medication therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Balancing Selectivity and Efficacy of Bispecific Epidermal Growth Factor Receptor (EGFR) × c-MET Antibodies and Antibody-Drug Conjugates*

PubMed Central

Sellmann, Carolin; Doerner, Achim; Knuehl, Christine; Rasche, Nicolas; Sood, Vanita; Krah, Simon; Rhiel, Laura; Messemer, Annika; Wesolowski, John; Schuette, Mark; Becker, Stefan; Toleikis, Lars; Kolmar, Harald; Hock, Bjoern

2016-01-01

Bispecific antibodies (bsAbs) and antibody-drug conjugates (ADCs) have already demonstrated benefits for the treatment of cancer in several clinical studies, showing improved drug selectivity and efficacy. In particular, simultaneous targeting of prominent cancer antigens, such as EGF receptor (EGFR) and c-MET, by bsAbs has raised increasing interest for potentially circumventing receptor cross-talk and c-MET-mediated acquired resistance during anti-EGFR monotherapy. In this study, we combined the selectivity of EGFR × c-MET bsAbs with the potency of cytotoxic agents via bispecific antibody-toxin conjugation. Affinity-attenuated bispecific EGFR × c-MET antibody-drug conjugates demonstrated high in vitro selectivity toward tumor cells overexpressing both antigens and potent anti-tumor efficacy. Due to basal EGFR expression in the skin, ADCs targeting EGFR in general warrant early safety assessments. Reduction in EGFR affinity led to decreased toxicity in keratinocytes. Thus, the combination of bsAb affinity engineering with the concept of toxin conjugation may be a viable route to improve the safety profile of ADCs targeting ubiquitously expressed antigens. PMID:27694443

Verifying community-wide exposure to endocrine disruptors in personal care products - In quest for metabolic biomarkers of exposure via in vitro studies and wastewater-based epidemiology.

PubMed

Lopardo, Luigi; Adams, David; Cummins, Andrew; Kasprzyk-Hordern, Barbara

2018-06-14

This study aimed to identify human specific metabolites of selected known or suspected endocrine disruptors (EDCs), mainly UV filters, used in personal care and consumer products whose metabolism has hardly been explored and to select suitable candidate biomarkers for human exposure studies using wastewater based epidemiology (WBE). The analysis of metabolic biomarkers of target chemicals is crucial in order to distinguish between internal and external exposure, since many sources contribute to chemicals being discharged into wastewater. This was achieved through the employment of a new analytical framework for verification of biomarkers of exposure to chemicals combining human biomonitoring and water fingerprinting. Eight EDCs with unknown metabolic pathways (benzophenone-1 (BP-1); benzophenone-2 (BP-2); 4,4'-dihydroxybenzophenone (4,4'-DHBP); 4-benzylphenol (4-BenzPh); homosalate (HO); octocrylene (OC); 3-benzylidene camphor (3-BC), and two EDCs with known metabolism (bisphenol A (BPA) and benzophenone-3 (BP-3)) were tested. The biotransformation observed consisted mainly of phase I processes such as hydrolysis and hydroxylation together with phase II conjugation reactions such as sulphation and glucuronidation. Only two chemicals (BP-1, BP-3) were identified in urine and three chemicals (BPA, BP-1, BP-3) in wastewater. Five newly discovered metabolites (HO-Met1, OC-Met1, 4-BenzPh-Met4, 4-BenzPh-Met5 and 4-BenzPh-Met6) and one previously known metabolite (BPA-Met3) were detected in tested urine/wastewater samples from five WWTPs serving large communities ranging between 17 and 100 thousand inhabitants. The presence of metabolic biotransformation products of OC, 4-BenzPh, BPA and HO in wastewater provides evidence for internal exposure of studied populations to these chemicals. Copyright © 2018 Elsevier Ltd. All rights reserved.

Easy and low-cost identification of metabolic syndrome in patients treated with second-generation antipsychotics: artificial neural network and logistic regression models.

PubMed

Lin, Chao-Cheng; Bai, Ya-Mei; Chen, Jen-Yeu; Hwang, Tzung-Jeng; Chen, Tzu-Ting; Chiu, Hung-Wen; Li, Yu-Chuan

2010-03-01

Metabolic syndrome (MetS) is an important side effect of second-generation antipsychotics (SGAs). However, many SGA-treated patients with MetS remain undetected. In this study, we trained and validated artificial neural network (ANN) and multiple logistic regression models without biochemical parameters to rapidly identify MetS in patients with SGA treatment. A total of 383 patients with a diagnosis of schizophrenia or schizoaffective disorder (DSM-IV criteria) with SGA treatment for more than 6 months were investigated to determine whether they met the MetS criteria according to the International Diabetes Federation. The data for these patients were collected between March 2005 and September 2005. The input variables of ANN and logistic regression were limited to demographic and anthropometric data only. All models were trained by randomly selecting two-thirds of the patient data and were internally validated with the remaining one-third of the data. The models were then externally validated with data from 69 patients from another hospital, collected between March 2008 and June 2008. The area under the receiver operating characteristic curve (AUC) was used to measure the performance of all models. Both the final ANN and logistic regression models had high accuracy (88.3% vs 83.6%), sensitivity (93.1% vs 86.2%), and specificity (86.9% vs 83.8%) to identify MetS in the internal validation set. The mean +/- SD AUC was high for both the ANN and logistic regression models (0.934 +/- 0.033 vs 0.922 +/- 0.035, P = .63). During external validation, high AUC was still obtained for both models. Waist circumference and diastolic blood pressure were the common variables that were left in the final ANN and logistic regression models. Our study developed accurate ANN and logistic regression models to detect MetS in patients with SGA treatment. The models are likely to provide a noninvasive tool for large-scale screening of MetS in this group of patients. (c) 2010 Physicians Postgraduate Press, Inc.

School lunch: a comparison of the fat and cholesterol content with dietary guidelines.

PubMed

Whitaker, R C; Wright, J A; Finch, A J; Deyo, R A; Psaty, B M

1993-12-01

To compare the fat and cholesterol content of the foods offered and selected in an elementary school lunch program with current dietary guidelines. For 105 school days we recorded the food items selected by elementary school students in an entire school district (262,851 meals) who were given a choice between two entrees. The nutrient content of foods was assessed with a computerized nutrient data base supplemented by the food manufacturers' data. Sixteen elementary schools in the Bellevue (Washington) School District. The number of students eating school lunch averaged 2500 per day, of whom 25% were from households with incomes less than 185% of poverty. None. We determined the nutritional content of the average meal selected; the proportion of days when one of the two offered entrees met fat and cholesterol guidelines; and the proportion of children selecting the entrees that met the guidelines. The average lunch selected had 35.9% of calories from total fat and 12.6% from saturated fat, exceeding the guidelines of 30% and 10%, respectively. Lunch contained an average of 57 mg cholesterol (106 mg/1000 kcal) and met guidelines. One of the two daily entree choices met guidelines for both total fat and saturated fat on 20% of days, and met both fat and cholesterol guidelines on 14% of days. When available, entrees meeting the fat guidelines were chosen by 37% of students, and entrees meeting both fat and cholesterol guidelines were chosen by 34% of students. In this school district the average lunch selected did not meet the current guidelines for dietary fat; when given the choice, more than one third of students selected the entrees that met these guidelines.

Evaluation of microRNAs − 208 and 133a/b as differential biomarkers of acute cardiac and skeletal muscle toxicity in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Calvano, Jacqueline, E-mail: Jacqueline.Calvano@bm

Conventional circulating biomarkers of cardiac and skeletal muscle (SKM) toxicity lack specificity and/or have a short half-life. MicroRNAs (miRNAs) are currently being assessed as biomarkers of tissue injury based on their long half-life in blood and selective expression in certain tissues. To assess the utility of miRNAs as biomarkers of cardiac and SKM injury, male Sprague–Dawley rats received a single dose of isoproterenol (ISO); metaproterenol (MET); allylamine (AAM); mitoxantrone (MIT); acetaminophen (APAP) or vehicle. Blood and tissues were collected from rats in each group at 4, 24 and 48 h. ISO, MET, and AAM induced cardiac and SKM lesions andmore » APAP induced liver specific lesions. There was no evidence of tissue injury with MIT by histopathology. Serum levels of candidate miRNAs were compared to conventional serum biomarkers of SKM/cardiac toxicity. Increases in heart specific miR-208 only occurred in rats with cardiac lesions alone and were increased for a longer duration than cardiac troponin and FABP3 (cardiac biomarkers). ISO, MET and AAM induced increases in MyL3 and skeletal muscle troponin (sTnl) (SKM biomarkers). MIT induced large increases in sTnl indicative of SKM toxicity, but sTnl levels were also increased in APAP-treated rats that lacked SKM toxicity. Serum levels of miR-133a/b (enriched in cardiac and SKM) increased following ISO, MET, AAM and MIT treatments but were absent in APAP-treated rats. Our results suggest that miR-133a/b are sensitive and specific markers of SKM and cardiac toxicity and that miR-208 used in combination with miR-133a/b can be used to differentiate cardiac from SKM toxicity. - Highlights: • MiR-208 is specifically expressed in rat hearts. • MiR-133a/b are enriched in rat cardiac/skeletal muscle. • MiR-133a/b are sensitive and specific markers of muscle/cardiac toxicity. • MiR-208 can be used to differentiate cardiac toxicity from skeletal muscle toxicity.« less

A retrospective analysis of episodes of single tooth extraction under general anaesthesia for adults.

PubMed

Hong, B; Birnie, A

2016-01-15

To investigate the provision of adult dental extraction under general anaesthesia (DGA) at the Royal Cornwall Hospitals NHS Trust (RCHT)-- specifically adult single tooth DGA episodes in regards to numbers, demographics, justifications, and appropriateness regarding the use of resources. Data were collected retrospectively from the patient case notes and electronic records for the complete study cohort. This study included all episodes of adult single tooth DGA in all RCHT sites during 2014, except for mandibular third molar and impacted teeth. Each case was tested against the DGA case selection criteria empirically devised for this study. In 2014, 106 episodes of adult single tooth DGA were carried out in RCHT that met the inclusion criteria. Younger females from more socio-economically deprived areas of Cornwall were increasingly likely to have this procedure. Mental disorders were the most prevalent co-morbidity (21.7%) in this cohort. The vast majority of patients (93.4%) had previously tolerated dental treatment without the need for general anaesthesia (GA). Many referrals (46.2%) and listings (30.2%) specifically stated patient demand-driven reasons. None of the cohort had DGA due to failure of sedation. There were potentially 11 episodes that met the DGA case selection criteria. Patients waited for 126 days (median) from the referral date for an operation which took seven minutes (median) to complete. The majority (83%) of the cases were simple exodontia. Twenty patients (18.9%) had previous DGA. Potentially a considerable proportion of GA prescription appeared to be driven by patient demand rather than clinical need. This study poses a fundamental question--what drives the demand for DGA? National data collection and specific DGA case selection criteria are recommended.

Instability of different adolescent metabolic syndrome definitions tracked into early adulthood metabolic syndrome: Tehran Lipid and Glucose Study (TLGS).

PubMed

Asghari, Golaleh; Eftekharzadeh, Anita; Hosseinpanah, Farhad; Ghareh, Sahar; Mirmiran, Parvin; Azizi, Fereidoun

2017-02-01

There are substantial controversies about the clinical utility of adolescent metabolic syndrome (MetS). The current study examined the stability of adolescent MetS by assessing the agreement and discriminative abilities of four different definitions of adolescent MetS and the adult MetS definition during a 10.4-yr follow up. For this study, 1424 adolescents (55.2% female), who participated in the framework of the Tehran Lipid and Glucose Study were included. Kappa was calculated for agreement between adolescent MetS definitions [Cook, de Ferranti, pediatric National Cholesterol Education Program (NCEP) and pediatric International Diabetes Federation (IDF)] and the adulthood MetS definition defined by the joint interim statement (JIS) criteria. MetS persistence, instability, and incidence were assessed, and for each of the four adolescent definitions, sensitivity, specificity, and area under receiver operating curve (AUC) for the counting of categorical adulthood MetS components was evaluated. The agreement between the four adolescent MetS definitions and JIS was poor (κ = 0.094-0.255). All definitions showed low sensitivity and high specificity, except for de Ferranti's, which contrary to other definitions, had higher sensitivity and lower specificity. All four adolescent definitions revealed generally low AUCs (0.601-0.647). Compared with the pubertal group (11-14 yr), the predictive power was slightly higher in the late-pubertal group (15-18 yr). Cook's and de Ferranti's definitions showed fairly better predictive powers (0.647 and 0.644, respectively). Across all definitions, instability ranged between 5.4 and 19.6%. The adolescent definitions show considerable amount of instability defined as poor agreement and low discriminative abilities tracked into early adulthood. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A Genetically Encoded AND Gate for Cell-Targeted Metabolic Labeling of Proteins

PubMed Central

Mahdavi, Alborz; Segall-Shapiro, Thomas H.; Kou, Songzi; Jindal, Granton A.; Hoff, Kevin G.; Liu, Shirley; Chitsaz, Mohsen; Ismagilov, Rustem F.; Silberg, Jonathan J.; Tirrell, David A.

2013-01-01

We describe a genetic AND gate for cell-targeted metabolic labeling and proteomic analysis in complex cellular systems. The centerpiece of the AND gate is a bisected methionyl-tRNA synthetase (MetRS) that charges the Met surrogate azidonorleucine (Anl) to tRNAMet. Cellular protein labeling occurs only upon activation of two different promoters that drive expression of the N- and C-terminal fragments of the bisected MetRS. Anl-labeled proteins can be tagged with fluorescent dyes or affinity reagents via either copper-catalyzed or strain-promoted azide-alkyne cycloaddition. Protein labeling is apparent within five minutes after addition of Anl to bacterial cells in which the AND gate has been activated. This method allows spatial and temporal control of proteomic labeling and identification of proteins made in specific cellular subpopulations. The approach is demonstrated by selective labeling of proteins in bacterial cells immobilized in the center of a laminar-flow microfluidic channel, where they are exposed to overlapping, opposed gradients of inducers of the N- and C-terminal MetRS fragments. The observed labeling profile is predicted accurately from the strengths of the individual input signals. PMID:23406315

Incorporation of Methionine Analogues Into Bombyx mori Silk Fibroin for Click Modifications.

PubMed

Teramoto, Hidetoshi; Kojima, Katsura

2015-05-01

Bombyx mori silk fibroin incorporating three methionine (Met) analogues-homopropargylglycine (Hpg), azidohomoalanine (Aha), and homoallylglycine (Hag)-can be produced simply by adding them to the diet of B. mori larvae. The Met analogues are recognized by methionyl-tRNA synthetase, bound to tRNA(Met), and used for the translation of adenine-uracil-guanine (AUG) codons competitively with Met. In the presence of the standard amount of Met in the diet, incorporation of these analogues remains low. Lowering the amount of Met in the diet drastically improves incorporation efficiencies. Alkyne and azide groups in Hpg and Aha incorporated into silk fibroin can be selectively modified with Cu-catalyzed azide-alkyne cycloaddition reactions (click chemistry). Since Met residues exist only at the N-terminal domain of the fibroin heavy chain and in the fibroin light chain, good access to the reactive sites is expected and domain-selective modifications are possible without perturbing other major domains, including repetitive domains. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The Link of Self-Reported Insomnia Symptoms and Sleep Duration with Metabolic Syndrome: A Chinese Population-Based Study

PubMed Central

Lin, Shih-Chieh; Sun, Chien-An; You, San-Lin; Hwang, Lee-Ching; Liang, Chun-Yu; Yang, Tsan; Bai, Chyi-Huey; Chen, Chien-Hua; Wei, Cheng-Yu; Chou, Yu-Ching

2016-01-01

Study Objectives: The aims of this study are to investigate the relationships of metabolic syndrome (MetS) with insomnia symptoms and sleep duration in a Chinese adult population. Methods: Data from a nationwide epidemiological survey conducted on residents from randomly selected districts in Taiwan in 2007 were used for this cross-sectional population-based study. A total of 4,197 participants were included in this study. Insomnia symptoms, including difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), early morning awakening (EMA), were assessed using the Insomnia Self-Assessment Inventory questionnaire. Subjects were divided into 3 groups based upon their reported sleep duration (< 7, 7–8, and ≥ 9 h per night). Odds ratios (ORs) and 95% confidence intervals (CIs) derived from multivariable logistic regression were used to evaluate the study aims. Results: The endorsement of DIS and DMS were cross-sectionally associated with the MetS after adjustment for sleep duration (OR [95% CI] was 1.24 [1.01–1.51] and 1.28 [1.02–1.61], respectively). In addition, short sleep duration was significantly associated with the prevalence of MetS independent of insomnia symptoms (OR [95% CI] was 1.54 [1.05–2.47]). However, there was no significant combined effect of insomnia symptoms and sleep duration on the prevalence of MetS. Conclusions: The current investigation shows that short sleep duration and insomnia symptoms, specifically DIS and DMS, were significant correlates of MetS. These findings should be replicated in prospective studies using both sleep duration and sleep quality measures. Citation: Lin SC, Sun CA, You SL, Hwang LC, Liang CY, Yang T, Bai CH, Chen CH, Wei CY, Chou YC. The link of self-reported insomnia symptoms and sleep duration with metabolic syndrome: a Chinese population-based study. SLEEP 2016;39(6):1261–1266. PMID:27070137

Using Semantic Components to Represent Dynamics of an Interdisciplinary Healthcare Team in a Multi-Agent Decision Support System.

PubMed

Wilk, Szymon; Kezadri-Hamiaz, Mounira; Rosu, Daniela; Kuziemsky, Craig; Michalowski, Wojtek; Amyot, Daniel; Carrier, Marc

2016-02-01

In healthcare organizations, clinical workflows are executed by interdisciplinary healthcare teams (IHTs) that operate in ways that are difficult to manage. Responding to a need to support such teams, we designed and developed the MET4 multi-agent system that allows IHTs to manage patients according to presentation-specific clinical workflows. In this paper, we describe a significant extension of the MET4 system that allows for supporting rich team dynamics (understood as team formation, management and task-practitioner allocation), including selection and maintenance of the most responsible physician and more complex rules of selecting practitioners for the workflow tasks. In order to develop this extension, we introduced three semantic components: (1) a revised ontology describing concepts and relations pertinent to IHTs, workflows, and managed patients, (2) a set of behavioral rules describing the team dynamics, and (3) an instance base that stores facts corresponding to instances of concepts from the ontology and to relations between these instances. The semantic components are represented in first-order logic and they can be automatically processed using theorem proving and model finding techniques. We employ these techniques to find models that correspond to specific decisions controlling the dynamics of IHT. In the paper, we present the design of extended MET4 with a special focus on the new semantic components. We then describe its proof-of-concept implementation using the WADE multi-agent platform and the Z3 solver (theorem prover/model finder). We illustrate the main ideas discussed in the paper with a clinical scenario of an IHT managing a patient with chronic kidney disease.

KRC-327, a selective novel inhibitor of c-Met receptor tyrosine kinase with anticancer activity.

PubMed

Park, Byung Hee; Jung, Kyung Hee; Yun, Sun-Mi; Hong, Sang-Won; Ryu, Jae Wook; Jung, Heejung; Ha, Jae Du; Lee, Jongkook; Hong, Soon-Sun

2013-05-01

c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been reported to be involved in tumorigenesis and metastatic progression. We synthesized a novel triazolopyridazine derivative KRC-327 which selectively targets the c-Met. When we performed receptor tyrosine kinases (RTKs) array with 42 different phosphorylated-RTKs, KRC-327 strongly inhibited expression of activated c-Met in MKN-45 cancer cells. This was confirmed by immunofluorescence staining. Also, KRC-327 decreased the expression of Gab1, Akt, signal transducer and activator of transcription 3 (STAT3) and Erk, down-stream signals of c-Met. KRC-327 strongly suppressed the growth of c-Met over-expressed cancer cells (MKN-45, SNU-638, SNU-5), while not in c-Met absent cancer cell lines (MKN-1, SNU-1). Furthermore, KRC-327 effectively induced cell cycle arrest, especially G0/G1 arrest by increasing expression of p21, p27 and decreasing that of cyclin D1. In the ligand-induced functional studies, KRC-327 inhibited proliferation of HGF-stimulated BxPC-3 cells, the migration of HGF-stimulated AGS cancer cells, and suppressed colony formation in HGF-stimulated U-87MG cells. In xenograft animal models, KRC-327 significantly not only delayed tumor growth but also suppressed phosphorylation of c-Met and its signaling cascades as well as proliferation. Taken together, these results demonstrate that KRC-327 selectively targets c-Met, resulting in inhibition of cell growth and proliferation. Therefore, we suggest that KRC-327 may be a novel drug candidate with the therapeutic potential of targeting c-Met in human cancer. Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.

Transcriptional regulation of the MET receptor tyrosine kinase gene by MeCP2 and sex-specific expression in autism and Rett syndrome

PubMed Central

Plummer, J T; Evgrafov, O V; Bergman, M Y; Friez, M; Haiman, C A; Levitt, P; Aldinger, K A

2013-01-01

Single nucleotide variants (SNV) in the gene encoding the MET receptor tyrosine kinase have been associated with an increased risk for autism spectrum disorders (ASD). The MET promoter SNV rs1858830 C ‘low activity' allele is enriched in ASD, associated with reduced protein expression, and impacts functional and structural circuit connectivity in humans. To gain insight into the transcriptional regulation of MET on ASD-risk etiology, we examined an interaction between the methyl CpG-binding protein 2 (MeCP2) and the MET 5′ promoter region. Mutations in MeCP2 cause Rett syndrome (RTT), a predominantly female neurodevelopmental disorder sharing some ASD clinical symptoms. MeCP2 binds to a region of the MET promoter containing the ASD-risk SNV, and displays rs1858830 genotype-specific binding in human neural progenitor cells derived from the olfactory neuroepithelium. MeCP2 binding enhances MET expression in the presence of the rs1858830 C allele, but MET transcription is attenuated by RTT-specific mutations in MeCP2. In the postmortem temporal cortex, a region normally enriched in MET, gene expression is reduced dramatically in females with RTT, although not due to enrichment of the rs1858830 C ‘low activity' allele. We newly identified a sex-based reduction in MET expression, with male ASD cases, but not female ASD cases compared with sex-matched controls. The experimental data reveal a prominent allele-specific regulation of MET transcription by MeCP2. The mechanisms underlying the pronounced reduction of MET in ASD and RTT temporal cortex are distinct and likely related to factors unique to each disorder, including a noted sex bias. PMID:24150225

Transcriptional regulation of the MET receptor tyrosine kinase gene by MeCP2 and sex-specific expression in autism and Rett syndrome.

PubMed

Plummer, J T; Evgrafov, O V; Bergman, M Y; Friez, M; Haiman, C A; Levitt, P; Aldinger, K A

2013-10-22

Single nucleotide variants (SNV) in the gene encoding the MET receptor tyrosine kinase have been associated with an increased risk for autism spectrum disorders (ASD). The MET promoter SNV rs1858830 C 'low activity' allele is enriched in ASD, associated with reduced protein expression, and impacts functional and structural circuit connectivity in humans. To gain insight into the transcriptional regulation of MET on ASD-risk etiology, we examined an interaction between the methyl CpG-binding protein 2 (MeCP2) and the MET 5' promoter region. Mutations in MeCP2 cause Rett syndrome (RTT), a predominantly female neurodevelopmental disorder sharing some ASD clinical symptoms. MeCP2 binds to a region of the MET promoter containing the ASD-risk SNV, and displays rs1858830 genotype-specific binding in human neural progenitor cells derived from the olfactory neuroepithelium. MeCP2 binding enhances MET expression in the presence of the rs1858830 C allele, but MET transcription is attenuated by RTT-specific mutations in MeCP2. In the postmortem temporal cortex, a region normally enriched in MET, gene expression is reduced dramatically in females with RTT, although not due to enrichment of the rs1858830 C 'low activity' allele. We newly identified a sex-based reduction in MET expression, with male ASD cases, but not female ASD cases compared with sex-matched controls. The experimental data reveal a prominent allele-specific regulation of MET transcription by MeCP2. The mechanisms underlying the pronounced reduction of MET in ASD and RTT temporal cortex are distinct and likely related to factors unique to each disorder, including a noted sex bias.

(18)F-FBPA as a tumor specific tracer of L-type amino acid transporter 1 (LAT1): PET evaluation in tumor and inflammation compared to (18)F-FDG and (11)C-methionine.

PubMed

Watabe, Tadashi; Hatazawa, Jun

2015-01-01

(18)F-FDG-PET is used worldwide for oncology patients. However, we sometimes encounter false positive cases of (18)F-FDG PET, such as moderate uptake in the inflammatory lesion, because (18)F-FDG accumulates not only in the cancer cells but also in the inflammatory cells (macrophage, granulation tissue, etc). To overcome this limitation of (18)F-FDG, we started to use (4-borono-2- [(18)F]fluoro-L-phenylalanine) (18)F-FBPA, an artificial amino acid tracer which is focusing attention as a tumor specific PET tracer. Physiological accumulation of (18)F-FBPA is limited in the kidney and urinary tract in humans, which enable preferable evaluation of uptake in the abdominal organs compared to (11)C-methionine ((11)C-MET). The purpose of this study was to evaluate (18)F-FBPA as a tumor specific tracer by in vitro cellular uptake analysis focusing on the selectivity of L-type amino acid transporter 1 (LAT1), which is specifically expressed in tumor cells, and in vivo PET analysis in rat xenograft and inflammation models compared to (18)F-FDG and (11)C-methionine. Uptake inhibition and efflux experiments were performed in HEK293-LAT1 and LAT2 cells using cold BPA, cold (18)F-FBPA, and hot (18)F-FBPA to evaluate LAT affinity and transport capacity. Position emission tomography studies were performed in rat xenograft model of C6 glioma 2 weeks after the implantation (n=9, body weight=197±10.5g) and subcutaneous inflammation model 4 days after the injection of turpentine oil (n=9, body weight=197±14.4g). Uptake on static PET images were compared among (18)F-FBPA at 60-70min post injection, (18)F-FDG at 60-70min, and (11)C-MET at 20-30min in the tumors and the inflammatory lesions by maximum standardized uptake value (SUVmax). Cellular uptake analysis showed no significant difference in inhibitory effect and efflux of LAT1 between cold (18)F-FBPA and cold BPA, suggesting the same affinity and transport capacity via LAT1. Uptake of (18)F-FBPA via LAT1 was superior to LAT2 by the concentration dependent uptake analysis. Position emission tomography analysis using SUVmax showed significantly higher accumulation of (18)F-FDG in the tumor and the inflammatory lesions (7.19±2.11 and 4.66±0.63, respectively) compared to (18)F-FBPA (3.23±0.40 and 1.86±0.19, respectively) and (11)C-MET (3.39±0.43 and 1.63±0.11, respectively) (P<0.01 by Tukey test). No significant difference was observed between (18)F-FBPA and (11)C-MET. (18)F-FBPA showed high selectivity of LAT1 by in vitro cellular uptake analysis, suggesting the potential as a tumor-specific substrate. In vivo PET analysis showed significantly lower uptake of (18)F-FBPA and (11)C-MET in the inflammatory lesions compared to (18)F-FDG, suggesting comparable utility of (18)F-FBPA PET to (11)C-MET PET in differentiating between the tumor and the inflammation.

User's design handbook for a Standardized Control Module (SCM) for DC to DC Converters, volume 2

NASA Technical Reports Server (NTRS)

Lee, F. C.

1980-01-01

A unified design procedure is presented for selecting the key SCM control parameters for an arbitrarily given power stage configuration and parameter values, such that all regulator performance specifications can be met and optimized concurrently in a single design attempt. All key results and performance indices, for buck, boost, and buck/boost switching regulators which are relevant to SCM design considerations are included to facilitate frequent references.

Development of a large color range for a paint company

NASA Astrophysics Data System (ADS)

McGinley, Peter

2002-06-01

Experience with the Master Palette system of 6000 colors lead to a specification for a new color range where the primary design feature is the control of the paint tint formula. This design approach met a market-derived requirement for sample pots and fractional-strength colors. The layout process employed was able to display the color capability of the paint system and generate an array of colors with controlled spacing similar to Master Palette. Updated pigment selections and the introduction of additional colored bases completed the system specification of improved opacity and every color being exterior durable.

Mutations at the S1 sites of methionine aminopeptidases from Escherichia coli and Homo sapiens reveal the residues critical for substrate specificity.

PubMed

Li, Jing-Ya; Cui, Yong-Mei; Chen, Ling-Ling; Gu, Min; Li, Jia; Nan, Fa-Jun; Ye, Qi-Zhuang

2004-05-14

Methionine aminopeptidase (MetAP) catalyzes the removal of methionine from newly synthesized polypeptides. MetAP carries out this cleavage with high precision, and Met is the only natural amino acid residue at the N terminus that is accepted, although type I and type II MetAPs use two different sets of residues to form the hydrophobic S1 site. Characteristics of the S1 binding pocket in type I MetAP were investigated by systematic mutation of each of the seven S1 residues in Escherichia coli MetAP type I (EcMetAP1) and human MetAP type I (HsMetAP1). We found that Tyr-65 and Trp-221 in EcMetAP1, as well as the corresponding residues Phe-197 and Trp-352 in HsMetAP1, were essential for the hydrolysis of a thiopeptolide substrate, Met-S-Gly-Phe. Mutation of Phe-191 to Ala in HsMetAP1 caused inactivity in contrast to the full activity of EcMetAP1(Y62A), which may suggest a subtle difference between the two type I enzymes. The more striking finding is that mutation of Cys-70 in EcMetAP1 or Cys-202 in HsMetAP1 opens up the S1 pocket. The thiopeptolides Leu-S-Gly-Phe and Phe-S-Gly-Phe, with previously unacceptable Leu or Phe as the N-terminal residue, became efficient substrates of EcMetAP1(C70A) and HsMetAP1(C202A). The relaxed specificity shown in these S1 site mutants for the N-terminal residues was confirmed by hydrolysis of peptide substrates and inhibition by reaction products. The structural features at the enzyme active site will be useful information for designing specific MetAP inhibitors for therapeutic applications.

Optimal Waist-to-Height Ratio Values for Cardiometabolic Risk Screening in an Ethnically Diverse Sample of South African Urban and Rural School Boys and Girls

PubMed Central

Matsha, Tandi E.; Kengne, Andre-Pascal; Yako, Yandiswa Y.; Hon, Gloudina M.; Hassan, Mogamat S.; Erasmus, Rajiv T.

2013-01-01

Background The proposed waist-to-height ratio (WHtR) cut-off of 0.5 is less optimal for cardiometabolic risk screening in children in many settings. The purpose of this study was to determine the optimal WHtR for children from South Africa, and investigate variations by gender, ethnicity and residence in the achieved value. Methods Metabolic syndrome (MetS) components were measured in 1272 randomly selected learners, aged 10–16 years, comprising of 446 black Africans, 696 mixed-ancestry and 130 Caucasians. The Youden’s index and the closest-top-left (CTL) point approaches were used to derive WHtR cut-offs for diagnosing any two MetS components, excluding the waist circumference. Results The two approaches yielded similar cut-off in girls, 0.465 (sensitivity 50.0, specificity 69.5), but two different values in boys, 0.455 (42.9, 88.4) and 0.425 (60.3, 67.7) based on the Youden’s index and the CTL point, respectively. Furthermore, WHtR cut-off values derived differed substantially amongst the regions and ethnic groups investigated, whereby the highest cut-off was observed in semi-rural and white children, respectively, Youden’s index0.505 (31.6, 87.1) and CTL point 0.475 (44.4, 75.9). Conclusion The WHtR cut-off of 0.5 is less accurate for screening cardiovascular risk in South African children. The optimal value in this setting is likely gender and ethnicity-specific and sensitive to urbanization. PMID:23967160

Immunohistochemical application of a highly sensitive and specific murine monoclonal antibody recognising the extracellular domain of the human hepatocyte growth factor receptor (MET).

PubMed

Gruver, Aaron M; Liu, Ling; Vaillancourt, Peter; Yan, Sau-Chi B; Cook, Joel D; Roseberry Baker, Jessica A; Felke, Erin M; Lacy, Megan E; Marchal, Christophe C; Szpurka, Hadrian; Holzer, Timothy R; Rhoads, Emily K; Zeng, Wei; Wortinger, Mark A; Lu, Jirong; Chow, Chi-kin; Denning, Irene J; Beuerlein, Gregory; Davies, Julian; Hanson, Jeff C; Credille, Kelly M; Wijayawardana, Sameera R; Schade, Andrew E

2014-12-01

Development of novel targeted therapies directed against hepatocyte growth factor (HGF) or its receptor (MET) necessitates the availability of quality diagnostics to facilitate their safe and effective use. Limitations of some commercially available anti-MET antibodies have prompted development of the highly sensitive and specific clone A2H2-3. Here we report its analytical properties when applied by an automated immunohistochemistry method. Excellent antibody specificity was demonstrated by immunoblot, ELISA, and IHC evaluation of characterised cell lines including NIH3T3 overexpressing the related kinase MST1R (RON). Sensitivity was confirmed by measurements of MET in cell lines or characterised tissues. IHC correlated well with FISH and quantitative RT-PCR assessments of MET (P < 0.001). Good total agreement (89%) was observed with the anti-MET antibody clone SP44 using whole-tissue sections, but poor positive agreement (21-47%) was seen in tissue microarray cores. Multiple lots displayed appropriate reproducibility (R(2)  > 0.9). Prevalence of MET positivity by IHC was higher in non-squamous cell NSCLC, MET or EGFR amplified cases, and in tumours harbouring abnormalities in EGFR exon 19 or 21. The anti-MET antibody clone A2H2-3 displays excellent specificity and sensitivity. These properties make it suitable for clinical trial investigations and development as a potential companion diagnostic. © 2014 The Authors. Histopathology Published by John Wiley & Sons Ltd.

Neural network versus activity-specific prediction equations for energy expenditure estimation in children.

PubMed

Ruch, Nicole; Joss, Franziska; Jimmy, Gerda; Melzer, Katarina; Hänggi, Johanna; Mäder, Urs

2013-11-01

The aim of this study was to compare the energy expenditure (EE) estimations of activity-specific prediction equations (ASPE) and of an artificial neural network (ANNEE) based on accelerometry with measured EE. Forty-three children (age: 9.8 ± 2.4 yr) performed eight different activities. They were equipped with one tri-axial accelerometer that collected data in 1-s epochs and a portable gas analyzer. The ASPE and the ANNEE were trained to estimate the EE by including accelerometry, age, gender, and weight of the participants. To provide the activity-specific information, a decision tree was trained to recognize the type of activity through accelerometer data. The ASPE were applied to the activity-type-specific data recognized by the tree (Tree-ASPE). The Tree-ASPE precisely estimated the EE of all activities except cycling [bias: -1.13 ± 1.33 metabolic equivalent (MET)] and walking (bias: 0.29 ± 0.64 MET; P < 0.05). The ANNEE overestimated the EE of stationary activities (bias: 0.31 ± 0.47 MET) and walking (bias: 0.61 ± 0.72 MET) and underestimated the EE of cycling (bias: -0.90 ± 1.18 MET; P < 0.05). Biases of EE in stationary activities (ANNEE: 0.31 ± 0.47 MET, Tree-ASPE: 0.08 ± 0.21 MET) and walking (ANNEE 0.61 ± 0.72 MET, Tree-ASPE: 0.29 ± 0.64 MET) were significantly smaller in the Tree-ASPE than in the ANNEE (P < 0.05). The Tree-ASPE was more precise in estimating the EE than the ANNEE. The use of activity-type-specific information for subsequent EE prediction equations might be a promising approach for future studies.

Discovery of a new series of imidazo[1,2-a]pyridine compounds as selective c-Met inhibitors.

PubMed

Liu, Tong-Chao; Peng, Xia; Ma, Yu-Chi; Ji, Yin-Chun; Chen, Dan-Qi; Zheng, Ming-Yue; Zhao, Dong-Mei; Cheng, Mao-Sheng; Geng, Mei-Yu; Shen, Jing-Kang; Ai, Jing; Xiong, Bing

2016-05-01

Aberrant c-Met activation plays a critical role in cancer formation, progression and dissemination, as well as in development of resistance to anticancer drugs. Therefore, c-Met has emerged as an attractive target for cancer therapy. The aim of this study was to develop new c-Met inhibitors and elaborate the structure-activity relationships of identified inhibitors. Based on the predicted binding modes of Compounds 5 and 14 in docking studies, a new series of c-Met inhibitor-harboring 3-((1H-pyrrolo[3,2-c]pyridin-1-yl)sulfonyl)imidazo[1,2-a]pyridine scaffolds was discovered. Potent inhibitors were identified through extensive optimizations combined with enzymatic and cellular assays. A promising compound was further investigated in regard to its selectivity, its effects on c-Met signaling, cell proliferation and cell scattering in vitro. The most potent Compound 31 inhibited c-Met kinase activity with an IC50 value of 12.8 nmol/L, which was >78-fold higher than those of a panel of 16 different tyrosine kinases. Compound 31 (8, 40, 200 nmol/L) dose-dependently inhibited the phosphorylation of c-Met and its key downstream Akt and ERK signaling cascades in c-Met aberrant human EBC-1 cancer cells. In 12 human cancer cell lines harboring different background levels of c-Met expression/activation, Compound 31 potently inhibited c-Met-driven cell proliferation. Furthermore, Compound 31 dose-dependently impaired c-Met-mediated cell scattering of MDCK cells. This series of c-Met inhibitors is a promising lead for development of novel anticancer drugs.

Identifying the metabolic syndrome in obese children and adolescents: do age and definition matter?

PubMed

van Vliet, Mariska; von Rosenstiel, Inès A; Schindhelm, Roger K; Brandjes, Dees P M; Beijnen, Jos H; Diamant, Michaela

2009-09-01

To assess the prevalence of the metabolic syndrome (MetS) in overweight/obese children and adolescents of an out-patient clinic, and to compare two definitions of MetS in adolescents. In total, 528 overweight / obese children (3-16 years), of multi-ethnic origin, underwent an oral glucose tolerance test, blood collections and anthropometric measurements. In children <10 years, MetS was assessed according to child-specific cut-off values (MetS-child). In adolescents, MetS-child and MetS-adolescent (the recommendation of the International Diabetes Federation for adolescents) were compared. The prevalence of MetS-child within the cohort (median age 11.3, range 3.1-16.4 yrs) was 18.6% (children <10 years vs. adolescents: 14.1% vs. 20.7%, P=0.073). Insulin resistance was present in 47.7% (children <10 years vs. adolescents: 21.8% vs. 60.1%, P<0.001). MetS-child was highly prevalent, and not statistically significant between age groups. In adolescents, the prevalence of MetS-adolescent was higher than MetS-child (33.2% vs. 20.7%, P<0.001). The agreement between the MetS definitions was moderate (kappa =0.51), with the agreement for the MetS-criteria for abnormal lipid levels being substantial to very good (kappa =0.71 to 0.80). MetS-child was highly prevalent in overweight/obese children and adolescents. A higher prevalence of MetS according to adolescent- as compared to child-specific criteria was found.

In vivo detection of c-Met expression in a rat C6 glioma model.

PubMed

Towner, R A; Smith, N; Doblas, S; Tesiram, Y; Garteiser, P; Saunders, D; Cranford, R; Silasi-Mansat, R; Herlea, O; Ivanciu, L; Wu, D; Lupu, F

2008-01-01

The tyrosine kinase receptor, c-Met, and its substrate, the hepatocyte growth factor (HGF), are implicated in the malignant progression of glioblastomas. In vivo detection of c-Met expression may be helpful in the diagnosis of malignant tumours. The C6 rat glioma model is a widely used intracranial brain tumour model used to study gliomas experimentally. We used a magnetic resonance imaging (MRI) molecular targeting agent to specifically tag the cell surface receptor, c-Met, with an anti-c-Met antibody (Ab) linked to biotinylated Gd (gadolinium)-DTPA (diethylene triamine penta acetic acid)-albumin in rat gliomas to detect overexpression of this antigen in vivo. The anti-c-Met probe (anti-c-Met-Gd-DTPA-albumin) was administered intravenously, and as determined by an increase in MRI signal intensity and a corresponding decrease in regional T(1) relaxation values, this probe was found to detect increased expression of c-Met protein levels in C6 gliomas. In addition, specificity for the binding of the anti-c-Met contrast agent was determined by using fluorescence microscopic imaging of the biotinylated portion of the targeting agent within neoplastic and 'normal'brain tissues following in vivo administration of the anti-c-Met probe. Controls with no Ab or with a normal rat IgG attached to the contrast agent component indicated no non-specific binding to glioma tissue. This is the first successful visualization of in vivo overexpression of c-Met in gliomas.

In vivo detection of c-Met expression in a rat C6 glioma model

PubMed Central

Towner, RA; Smith, N; Doblas, S; Tesiram, Y; Garteiser, P; Saunders, D; Cranford, R; Silasi-Mansat, R; Herlea, O; Ivanciu, L; Wu, D; Lupu, F

2008-01-01

Abstract The tyrosine kinase receptor, c-Met, and its substrate, the hepatocyte growth factor (HGF), are implicated in the malignant progression of glioblastomas. In vivo detection of c-Met expression may be helpful in the diagnosis of malignant tumours. The C6 rat glioma model is a widely used intracranial brain tumour model used to study gliomas experimentally. We used a magnetic resonance imaging (MRI) molecular targeting agent to specifically tag the cell surface receptor, c-Met, with an anti-c-Met antibody (Ab) linked to biotinylated Gd (gadolinium)-DTPA (diethylene triamine penta acetic acid)-albumin in rat gliomas to detect overexpression of this antigen in vivo. The anti-c-Met probe (anti-c-Met-Gd-DTPA-albumin) was administered intravenously, and as determined by an increase in MRI signal intensity and a corresponding decrease in regional T1 relaxation values, this probe was found to detect increased expression of c-Met protein levels in C6 gliomas. In addition, specificity for the binding of the anti-c-Met contrast agent was determined by using fluorescence microscopic imaging of the biotinylated portion of the targeting agent within neoplastic and ‘normal’brain tissues following in vivo administration of the anti-c-Met probe. Controls with no Ab or with a normal rat IgG attached to the contrast agent component indicated no non-specific binding to glioma tissue. This is the first successful visualization of in vivo overexpression of c-Met in gliomas. PMID:18194445

Newborn Screening for Vitamin B6 Non-responsive Classical Homocystinuria: Systematical Evaluation of a Two-Tier Strategy.

PubMed

Okun, Jürgen G; Gan-Schreier, Hongying; Ben-Omran, Tawfeq; Schmidt, Kathrin V; Fang-Hoffmann, Junmin; Gramer, Gwendolyn; Abdoh, Ghassan; Shahbeck, Noora; Al Rifai, Hilal; Al Khal, Abdul Latif; Haege, Gisela; Chiang, Chuan-Chi; Kasper, David C; Wilcken, Bridget; Burgard, Peter; Hoffmann, Georg F

2017-01-01

In classical homocystinuria (HCU, MIM# 236200) due to the deficiency of cystathionine β-synthase (EC 4.2.1.22) there is a clear evidence for the success of early treatment. The aim of this study was to develop and evaluate a two-tier strategy for HCU newborn screening. We reevaluated data from our newborn screening programme for Qatar in a total number of 125,047 neonates including 30 confirmed HCU patients. Our hitherto existing screening strategy includes homocysteine (Hcy) measurements in every child, resulting in a unique dataset for evaluation of two-tier strategies. Reevaluation included methionine (Met) levels, Met to phenylalanine (Phe) ratio, and Hcy. Four HCU cases identified after database closure were also included in the evaluation. In addition, dried blood spot samples selected by Met values >P97 in the newborn screening programs in Austria, Australia, the Netherlands, and Taiwan were analyzed for Hcy. Met to Phe ratio was found to be more effective for first sieve than Met, sorting out nearly 90% of normal samples. Only 10% of the samples would have to be processed by second-tier measurement of Hcy in dried blood spots. As no patient with HCU was found neither in the samples investigated for HCU, nor by clinical diagnosis in the other countries, the generalization of our two-tier strategy could only be tested indirectly. The finally derived two-tier algorithm using Met to Phe ratio as first- and Hcy as second-tier requires 10% first-tier positives to be transferred to Hcy measurement, resulting in 100% sensitivity and specificity in HCU newborn screening.

Early Life Origins of Metabolic Syndrome: The Role of Environmental Toxicants

PubMed Central

Wang, Guoying; Chen, Zhu; Bartell, Tami; Wang, Xiaobin

2014-01-01

Metabolic syndrome (MetS) affects more than 47 million people in the U.S. Even more alarming, MetS, once regarded as an “adult problem”, has become increasingly common in children. To date, most related research and intervention efforts have occurred in the adult medicine arena, with limited understanding of the root causes and lengthy latency of MetS. This review highlights new science on the early life origins of MetS, with a particular focus on exposure to two groups of environmental toxicants: endocrine disrupting chemicals (EDCs) and metals during the prenatal and early postnatal periods, and their specific effects and important differences in the development of MetS. It also summarizes available data on epigenetic effects, including the role of EDCs in the androgen/estrogen pathways. Emerging evidence supports the link between exposures to environmental toxicants during early life and the development of MetS later in life. Additional research is needed to address important research gaps in this area, including prospective birth cohort studies to delineate temporal and dose-response relationships, important differences in the effects of various environmental toxicants and their joint effects on MetS, as well as epigenetic mechanisms underlying the effects of specific toxicants such as EDCs and metals. PMID:24883264

On the maintenance of sex chromosome polymorphism by sex-antagonistic selection.

PubMed

Blaser, Olivier; Neuenschwander, Samuel; Perrin, Nicolas

2011-10-01

Complex sex determination systems are a priori unstable and require specific selective forces for their maintenance. Analytical derivations suggest that sex antagonistic selection may play such a role, but this assumes absence of recombination between the sex-determining and sex-antagonistic genes. Using individual-based simulations and focusing on the sex chromosome and coloration polymorphisms of platy fishes as a case study, we show that the conditions for polymorphism maintenance induce female biases in primary sex ratios, so that sex ratio selection makes the system collapse toward male or female heterogamety as soon as recombinant genotypes appear. However, a polymorphism can still be maintained under scenarios comprising strong sexual selection against dull males, mild natural selection against bright females, and low recombination rates. Though such conditions are plausibly met in natural populations of fishes harboring such polymorphisms, quantitative empirical evaluations are required to properly test whether sex antagonistic selection is a causal agent or whether other selective processes are required (such as local mate competition favoring female-biased sex ratios).

Genomic Selection in Multi-environment Crop Trials.

PubMed

Oakey, Helena; Cullis, Brian; Thompson, Robin; Comadran, Jordi; Halpin, Claire; Waugh, Robbie

2016-05-03

Genomic selection in crop breeding introduces modeling challenges not found in animal studies. These include the need to accommodate replicate plants for each line, consider spatial variation in field trials, address line by environment interactions, and capture nonadditive effects. Here, we propose a flexible single-stage genomic selection approach that resolves these issues. Our linear mixed model incorporates spatial variation through environment-specific terms, and also randomization-based design terms. It considers marker, and marker by environment interactions using ridge regression best linear unbiased prediction to extend genomic selection to multiple environments. Since the approach uses the raw data from line replicates, the line genetic variation is partitioned into marker and nonmarker residual genetic variation (i.e., additive and nonadditive effects). This results in a more precise estimate of marker genetic effects. Using barley height data from trials, in 2 different years, of up to 477 cultivars, we demonstrate that our new genomic selection model improves predictions compared to current models. Analyzing single trials revealed improvements in predictive ability of up to 5.7%. For the multiple environment trial (MET) model, combining both year trials improved predictive ability up to 11.4% compared to a single environment analysis. Benefits were significant even when fewer markers were used. Compared to a single-year standard model run with 3490 markers, our partitioned MET model achieved the same predictive ability using between 500 and 1000 markers depending on the trial. Our approach can be used to increase accuracy and confidence in the selection of the best lines for breeding and/or, to reduce costs by using fewer markers. Copyright © 2016 Oakey et al.

Discovery of a new series of imidazo[1,2-a]pyridine compounds as selective c-Met inhibitors

PubMed Central

Liu, Tong-chao; Peng, Xia; Ma, Yu-chi; Ji, Yin-chun; Chen, Dan-qi; Zheng, Ming-yue; Zhao, Dong-mei; Cheng, Mao-sheng; Geng, Mei-yu; Shen, Jing-kang; Ai, Jing; Xiong, Bing

2016-01-01

Aim: Aberrant c-Met activation plays a critical role in cancer formation, progression and dissemination, as well as in development of resistance to anticancer drugs. Therefore, c-Met has emerged as an attractive target for cancer therapy. The aim of this study was to develop new c-Met inhibitors and elaborate the structure-activity relationships of identified inhibitors. Methods: Based on the predicted binding modes of Compounds 5 and 14 in docking studies, a new series of c-Met inhibitor-harboring 3-((1H-pyrrolo[3,2-c]pyridin-1-yl)sulfonyl)imidazo[1,2-a]pyridine scaffolds was discovered. Potent inhibitors were identified through extensive optimizations combined with enzymatic and cellular assays. A promising compound was further investigated in regard to its selectivity, its effects on c-Met signaling, cell proliferation and cell scattering in vitro. Results: The most potent Compound 31 inhibited c-Met kinase activity with an IC50 value of 12.8 nmol/L, which was >78-fold higher than those of a panel of 16 different tyrosine kinases. Compound 31 (8, 40, 200 nmol/L) dose-dependently inhibited the phosphorylation of c-Met and its key downstream Akt and ERK signaling cascades in c-Met aberrant human EBC-1 cancer cells. In 12 human cancer cell lines harboring different background levels of c-Met expression/activation, Compound 31 potently inhibited c-Met-driven cell proliferation. Furthermore, Compound 31 dose-dependently impaired c-Met-mediated cell scattering of MDCK cells. Conclusion: This series of c-Met inhibitors is a promising lead for development of novel anticancer drugs. PMID:27041462

Analysis of cavitation damage on the Space Shuttle main engine high pressure oxidizer turbopump

NASA Technical Reports Server (NTRS)

Stinebring, D. R.

1985-01-01

The performance of the Space Shuttle Main Engines (SSME) has met or exceeded specifications. However, the durability for selected components has not met the desired lifetime criteria. Thus, the High-Pressure Oxidizer Turbopump (HPOTP) has experienced cavitation erosion problems in a number of locations in the pump. An investigation was conducted, taking into account an analysis of the cavitation damage, the development of a flow model for the pump, and the recommendation of design changes which would increase the life expectancy of the unit. The present paper is concerned with the cavitation damage analysis. A model is presented which relates the heavy damage on the housing and over the inducer blades to unsteady blade surface cavitation. This cavitation occurs on the inducer blades in the wakes downstream of the pump inlet housing vanes.

Can living donor liver transplantation offer similar outcomes to deceased donor liver transplantation using expanded selection criteria for hepatocellular carcinoma?

PubMed Central

Chen, Li-Ping; Li, Chuan; Wen, Tian-Fu; Yan, Lu-Nan; Li, Bo; Yang, Jia-Yin

2015-01-01

Objective: To compare the outcomes of living donor liver transplantation (LDLT) versus deceased donor liver transplantation (DDLT) for patients with hepatocellular carcinoma (HCC) in different selection criteria. Methods: Data of patients with HCC who underwent liver transplantation between 2005 and 2013 at our center were reviewed. Clinical data of LDLT recipients and DDLT recipients were compared. The postoperative recurrence-free survival (RFS) rate and overall survival (OS) rate after LDLT versus DDLT were compared in the Milan recipients, the University of California, San Francisco (UCSF) recipients, the up-to-seven recipients, the Hangzhou recipients and the Chengdu recipients. Results: Data of 255 patients were retrospectively reviewed in this study. Seventeen DDLT recipient and 9 LDLT recipients died during the perioperative period. Among the remaining 229 recipients (NLDLT=66, NDDLT=163), 96 patients met the Milan criteria, 123 recipients met the UCSF criteria, 135 patients met the up-to-seven criteria, 216 patients met the Hangzhou criteria, and 229 recipients met the Chengdu criteria. The overall RFS and OS rates of the Milan recipients, the UCSF recipients, the up-to-seven recipients, the Hangzhou recipients and the Chengdu recipients after LDLT and DDLT were all similar. Conclusion: Using well-studied selection criteria, LDLT offers similar outcomes to DDLT for patient with HCC, even using expanded selection criteria. PMID:26430399

Can living donor liver transplantation offer similar outcomes to deceased donor liver transplantation using expanded selection criteria for hepatocellular carcinoma?

PubMed

Chen, Li-Ping; Li, Chuan; Wen, Tian-Fu; Yan, Lu-Nan; Li, Bo; Yang, Jia-Yin

2015-01-01

To compare the outcomes of living donor liver transplantation (LDLT) versus deceased donor liver transplantation (DDLT) for patients with hepatocellular carcinoma (HCC) in different selection criteria. Data of patients with HCC who underwent liver transplantation between 2005 and 2013 at our center were reviewed. Clinical data of LDLT recipients and DDLT recipients were compared. The postoperative recurrence-free survival (RFS) rate and overall survival (OS) rate after LDLT versus DDLT were compared in the Milan recipients, the University of California, San Francisco (UCSF) recipients, the up-to-seven recipients, the Hangzhou recipients and the Chengdu recipients. Data of 255 patients were retrospectively reviewed in this study. Seventeen DDLT recipient and 9 LDLT recipients died during the perioperative period. Among the remaining 229 recipients (NLDLT=66, NDDLT=163), 96 patients met the Milan criteria, 123 recipients met the UCSF criteria, 135 patients met the up-to-seven criteria, 216 patients met the Hangzhou criteria, and 229 recipients met the Chengdu criteria. The overall RFS and OS rates of the Milan recipients, the UCSF recipients, the up-to-seven recipients, the Hangzhou recipients and the Chengdu recipients after LDLT and DDLT were all similar. Using well-studied selection criteria, LDLT offers similar outcomes to DDLT for patient with HCC, even using expanded selection criteria.

A first-in-human phase I study of SAR125844, a selective MET tyrosine kinase inhibitor, in patients with advanced solid tumours with MET amplification.

PubMed

Angevin, Eric; Spitaleri, Gianluca; Rodon, Jordi; Dotti, Katia; Isambert, Nicolas; Salvagni, Stefania; Moreno, Victor; Assadourian, Sylvie; Gomez, Corinne; Harnois, Marzia; Hollebecque, Antoine; Azaro, Analia; Hervieu, Alice; Rihawi, Karim; De Marinis, Filippo

2017-12-01

Dysregulated MET signalling is implicated in oncogenesis. The safety and preliminary efficacy of a highly selective MET kinase inhibitor (SAR125844) was investigated in patients with advanced solid tumours and MET dysregulation. This was a phase I dose-escalation (3 + 3 design [50-740 mg/m 2 ]) and dose-expansion study. In the dose escalation, patients had high total MET (t-MET) expression by immunohistochemistry (IHC) or MET amplification by fluorescence in situ hybridisation. In the dose expansion, patients had MET amplification (including a subset of patients with non-small cell lung cancer [NSCLC]) or phosphorylated-MET (p-MET) expression (IHC). Objectives were determination of maximum tolerated dose (MTD) of once-weekly intravenous SAR125844 based on dose-limiting toxicities; safety and pharmacokinetic profile; preliminary efficacy of SAR125844 MTD in the expansion cohort. In total, 72 patients were enrolled: dose escalation, N = 33; dose expansion, N = 39; 570 mg/m 2 was established as the MTD. Most frequent treatment-emergent adverse events (AEs) were asthenia/fatigue (58.3%), nausea (31.9%), and abdominal pain, constipation, and dyspnea (27.8% for each); 58.3% of patients reported grade 3 AEs (19.4% were treatment related). Of the 29 evaluable patients with MET amplification treated at 570 mg/m 2 , five achieved a partial response, including four of 22 with NSCLC; 17 patients had stable disease. No response was observed in patients with high p-MET solid tumours. There was no correlation between tumour response and t-MET status or MET gene copy number. The MTD of once-weekly SAR125844 was 570 mg/m 2 ; SAR125844 was well tolerated, with significant antitumour activity in patients with MET-amplified NSCLC. NCT01391533. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Discovery and Pharmacokinetic and Pharmacological Properties of the Potent and Selective MET Kinase Inhibitor 1-{6-[6-(4-Fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]benzothiazol-2-yl}-3-(2-morpholin-4-ylethyl)urea (SAR125844).

PubMed

Ugolini, Antonio; Kenigsberg, Mireille; Rak, Alexey; Vallée, Francois; Houtmann, Jacques; Lowinski, Maryse; Capdevila, Cécile; Khider, Jean; Albert, Eva; Martinet, Nathalie; Nemecek, Conception; Grapinet, Sandrine; Bacqué, Eric; Roesner, Manfred; Delaisi, Christine; Calvet, Loreley; Bonche, Fabrice; Semiond, Dorothée; Egile, Coumaran; Goulaouic, Hélène; Schio, Laurent

2016-08-11

The HGF/MET pathway is frequently activated in a variety of cancer types. Several selective small molecule inhibitors of the MET kinase are currently in clinical evaluation, in particular for NSCLC, liver, and gastric cancer patients. We report herein the discovery of a series of triazolopyridazines that are selective inhibitors of wild-type (WT) MET kinase and several clinically relevant mutants. We provide insight into their mode of binding and report unprecedented crystal structures of the Y1230H variant. A multiparametric chemical optimization approach allowed the identification of compound 12 (SAR125844) as a development candidate. In this chemical series, absence of CYP3A4 inhibition was obtained at the expense of satisfactory oral absorption. Compound 12, a promising parenteral agent for the treatment of MET-dependent cancers, promoted sustained target engagement at tolerated doses in a human xenograft tumor model. Preclinical pharmacokinetics conducted in several species were predictive for the observed pharmacokinetic behavior of 12 in cancer patients.

Genetic analysis of candidate SNPs for metabolic syndrome in obstructive sleep apnea (OSA)

PubMed Central

Grilo, Antonio; Ruiz-Granados, Elena S.; Moreno-Rey, Concha; Rivera, Jose M.; Ruiz, Agustin; Real, Luis M.; Sáez, Maria E.

2014-01-01

Obstructive sleep apnea (OSA) is a common disorder characterized by the reduction or complete cessation in airflow resulting from an obstruction of the upper airway. Several studies have observed an increased risk for cardiovascular morbidity and mortality among OSA patients. Metabolic syndrome (MetS), a cluster of cardiovascular risk factors characterized by the presence of insulin resistance, is often found in patients with OSA, but the complex interplay between these two syndromes is not well understood. In this study, we present the results of a genetic association analysis of 373 candidate SNPs for MetS selected in a previous genome wide association analysis (GWAS). The 384 selected SNPs were genotyped using the Illumina VeraCode Technology in 387 subjects retrospectively assessed at the Internal Medicine Unit of the “Virgen de Valme” University Hospital (Seville, Spain). In order to increase the power of this study and to validate our findings in an independent population, we used data from the Framingham Sleep study which comprises 368 individuals. Only the rs11211631 polymorphism was associated with OSA in both populations, with an estimated OR=0.57 (0.42-0.79) in the joint analysis (p=7.21 × 10-4). This SNP was selected in the previous GWAS for MetS components using a digenic approach, but was not significant in the monogenic study. We have also identified two SNPs (rs2687855 and rs4299396) with a protective effect from OSA only in the abdominal obese subpopulation. As a whole, our study does not support that OSA and MetS share major genetic determinants, although both syndromes share common epidemiological and clinical features. PMID:23524009

Does a brief suicide prevention gatekeeper training program enhance observed skills?

PubMed

Cross, Wendi; Matthieu, Monica M; Lezine, Dequincy; Knox, Kerry L

2010-01-01

Suicide is a significant public health problem worldwide that requires evidence-based prevention efforts. One approach to prevention is gatekeeper training. Gatekeeper training programs for community members have demonstrated positive changes in knowledge and attitudes about suicide. Changes in gatekeeper skills have not been well established. To assess and to predict the impact of a brief, gatekeeper training on community members' observed skills. Participants in a community gatekeeper training were employees at US universities. 50 participants were randomly selected for skills assessment and videotaped interacting with a standardized actor prior to and following training. Tapes were reliably rated for general and suicide-specific skills. Gatekeeper skills increased from pre- to posttest: 10% of participants met criteria for acceptable gatekeeper skills before training, while 54% met criteria after training. Pretraining variables did not predict increased skills. Results do not provide conclusions about the relationship between observed gatekeeper skills and actual use of those skills in the future. Gatekeeper training enhances suicide-specific skills for the majority of participants. Other strategies, such as behavioral rehearsal, may be necessary to enhance skills in the remaining participants.

cis-fumagillin, a new methionine aminopeptidase (type 2) inhibitor produced by Penicillium sp. F2757.

PubMed

Kwon, J Y; Jeong, H W; Kim, H K; Kang, K H; Chang, Y H; Bae, K S; Choi, J D; Lee, U C; Son, K H; Kwon, B M

2000-08-01

Selective inhibition against the yeast MetAP2 (methionine aminopeptidase type 2) was detected in the fermentation broth of a fungus F2757 that was later identified as Penicillium janczewskii. A new compound cis-fumagillin methyl ester (1) was isolated from the diazomethane treated fermentation extracts together with the known compound fumagillin methyl ester (2). The cis-fumagillin methyl ester, a stereoisomer of fumagillin methyl ester at the C2'-C3' position of the aliphatic side chain, selectively inhibited growth of the map1 mutant yeast strain (MetAP1 deletion strain) at a concentration as low as 1 ng. However, the wild type yeast w303 and the mutant map2 (MetAP2 deleted) strains were resistant up to 10 microg of the compound. In enzyme experiments, compound 1 inhibited the MetAP2 with an IC50 value of 6.3 nM, but it did not inhibit the MetAP1 (IC50 >200 microM). Compound 2 also inhibited the MetAP2 with an IC50 value of 9.2 nM and 105 microM against MetAP1.

Influence of body variables in the development of metabolic syndrome—A long term follow-up study

PubMed Central

Pavanello, Chiara; Zanaboni, Anna Maria; Gaito, Sabrina; Botta, Margherita; Mombelli, Giuliana; Sirtori, Cesare R.

2018-01-01

Objectives The body variable associated with the diagnosis of Metabolic Syndrome (MetS) is an elevated waist circumference (WC), although a number of other variables have been suggested. Among these, an elevated waist-to-height ratio (WHtR), ie a value higher than 0.5, that may identify abnormality, independently from height. An elevated WHtR provided the best correlation with MetS in a prior study in a large Italian population. In order to assess the validity of this conclusion, a long-term follow-up study re-examined this population, also in order to detect possible associations with cardiovascular (CV) risk. Methods and results 1,071 subjects with a complete follow-up of over 6 years were evaluated with a comparative assessment of the three anthropometric variables, namely WHtR, WC and body mass index (BMI). WHtR≥ 0.5 had the highest sensitivity for the identification of MetS, both in males and females (94.1% and 86.7% respectively). WHtR was of reduced specificity, occurring, yet less frequently (17.7% in males and 30% in females), in patients without MetS. By contrast, enlarged WC occurred with a lower frequency in male patients who developed MetS (30.2%) whereas in females, frequency was higher than in males (69.3%). Finally, a BMI≥ 25 kg/m2 had intermediate sensitivity and specificity regardless of gender. WC showed the highest odds ratio (2.62, 95%CI: 1.18–5.78) for the prediction of CV occurrence. Conclusion The present study confirms WHtR as an excellent screening tool in identifying MetS carriers, but, different from reports in other countries, it shows a lower specificity in our population. PMID:29432480

Influence of body variables in the development of metabolic syndrome-A long term follow-up study.

PubMed

Pavanello, Chiara; Zanaboni, Anna Maria; Gaito, Sabrina; Botta, Margherita; Mombelli, Giuliana; Sirtori, Cesare R; Ruscica, Massimiliano

2018-01-01

The body variable associated with the diagnosis of Metabolic Syndrome (MetS) is an elevated waist circumference (WC), although a number of other variables have been suggested. Among these, an elevated waist-to-height ratio (WHtR), ie a value higher than 0.5, that may identify abnormality, independently from height. An elevated WHtR provided the best correlation with MetS in a prior study in a large Italian population. In order to assess the validity of this conclusion, a long-term follow-up study re-examined this population, also in order to detect possible associations with cardiovascular (CV) risk. 1,071 subjects with a complete follow-up of over 6 years were evaluated with a comparative assessment of the three anthropometric variables, namely WHtR, WC and body mass index (BMI). WHtR≥ 0.5 had the highest sensitivity for the identification of MetS, both in males and females (94.1% and 86.7% respectively). WHtR was of reduced specificity, occurring, yet less frequently (17.7% in males and 30% in females), in patients without MetS. By contrast, enlarged WC occurred with a lower frequency in male patients who developed MetS (30.2%) whereas in females, frequency was higher than in males (69.3%). Finally, a BMI≥ 25 kg/m2 had intermediate sensitivity and specificity regardless of gender. WC showed the highest odds ratio (2.62, 95%CI: 1.18-5.78) for the prediction of CV occurrence. The present study confirms WHtR as an excellent screening tool in identifying MetS carriers, but, different from reports in other countries, it shows a lower specificity in our population.

Operational Use of OGC Web Services at the Met Office

NASA Astrophysics Data System (ADS)

Wright, Bruce

2010-05-01

The Met Office has adopted the Service-Orientated Architecture paradigm to deliver services to a range of customers through Rich Internet Applications (RIAs). The approach uses standard Open Geospatial Consortium (OGC) web services to provide information to web-based applications through a range of generic data services. "Invent", the Met Office beta site, is used to showcase Met Office future plans for presenting web-based weather forecasts, product and information to the public. This currently hosts a freely accessible Weather Map Viewer, written in JavaScript, which accesses a Web Map Service (WMS), to deliver innovative web-based visualizations of weather and its potential impacts to the public. The intention is to engage the public in the development of new web-based services that more accurately meet their needs. As the service is intended for public use within the UK, it has been designed to support a user base of 5 million, the analysed level of UK web traffic reaching the Met Office's public weather information site. The required scalability has been realised through the use of multi-tier tile caching: - WMS requests are made for 256x256 tiles for fixed areas and zoom levels; - a Tile Cache, developed in house, efficiently serves tiles on demand, managing WMS request for the new tiles; - Edge Servers, externally hosted by Akamai, provide a highly scalable (UK-centric) service for pre-cached tiles, passing new requests to the Tile Cache; - the Invent Weather Map Viewer uses the Google Maps API to request tiles from Edge Servers. (We would expect to make use of the Web Map Tiling Service, when it becomes an OGC standard.) The Met Office delivers specialist commercial products to market sectors such as transport, utilities and defence, which exploit a Web Feature Service (WFS) for data relating forecasts and observations to specific geographic features, and a Web Coverage Service (WCS) for sub-selections of gridded data. These are locally rendered as maps or graphs, and combined with the WMS pre-rendered images and text, in a FLEX application, to provide sophisticated, user impact-based view of the weather. The OGC web services supporting these applications have been developed in collaboration with commercial companies. Visual Weather was originally a desktop application for forecasters, but IBL have developed it to expose the full range of forecast and observation data through standard web services (WCS and WMS). Forecasts and observations relating to specific locations and geographic features are held in an Oracle Database, and exposed as a WFS using Snowflake Software's GO-Publisher application. The Met Office has worked closely with both IBL and Snowflake Software to ensure that the web services provided strike a balance between conformance to the standards and performance in an operational environment. This has proved challenging in areas where the standards are rapidly evolving (e.g. WCS) or do not allow adequate description of the Met-Ocean domain (e.g. multiple time coordinates and parametric vertical coordinates). It has also become clear that careful selection of the features to expose, based on the way in which you expect users to query those features, in necessary in order to deliver adequate performance. These experiences are providing useful 'real-world' input in to the recently launched OGC MetOcean Domain Working Group and World Meteorological Organisation (WMO) initiatives in this area.

PREVALENCE OF METABOLIC SYNDROME IN YOUNG MEXICANS: A SENSITIVITY ANALYSIS ON ITS COMPONENTS.

PubMed

Murguía-Romero, Miguel; Jiménez-Flores, J Rafael; Sigrist-Flores, Santiago C; Tapia-Pancardo, Diana C; Jiménez-Ramos, Arnulfo; Méndez-Cruz, A René; Villalobos-Molina, Rafael

2015-07-28

obesity is a worldwide epidemic, and the high prevalence of diabetes type II (DM2) and cardiovascular disease (CVD) is in great part a consequence of that epidemic. Metabolic syndrome is a useful tool to estimate the risk of a young population to evolve to DM2 and CVD. to estimate the MetS prevalence in young Mexicans, and to evaluate each parameter as an independent indicator through a sensitivity analysis. the prevalence of MetS was estimated in 6 063 young of the México City metropolitan area. A sensitivity analysis was conducted to estimate the performance of each one of the components of MetS, as an indicator of the presence of MetS itself. Five statistical of the sensitivity analysis were calculated for each MetS component and the other parameters included: sensitivity, specificity, positive predictive value or precision, negative predictive value, and accuracy. the prevalence of MetS in Mexican young population was estimated to be 13.4%. Waist circumference presented the highest sensitivity (96.8% women; 90.0% men), blood pressure presented the highest specificity for women (97.7%) and glucose for men (91.0%). When all the five statistical are considered triglycerides is the component with the highest values, showing a value of 75% or more in four of them. Differences by sex are detected for averages of all components of MetS in young without alterations. Mexican young are highly prone to acquire MetS: 71% have at least one and up to five MetS parameters altered, and 13.4% of them have MetS. From all the five components of MetS, waist circumference presented the highest sensitivity as a predictor of MetS, and triglycerides is the best parameter if a single factor is to be taken as sole predictor of MetS in Mexican young population, triglycerides is also the parameter with the highest accuracy. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

High temperature heat exchanger studies for applications to gas turbines

NASA Astrophysics Data System (ADS)

Min, June Kee; Jeong, Ji Hwan; Ha, Man Yeong; Kim, Kui Soon

2009-12-01

Growing demand for environmentally friendly aero gas-turbine engines with lower emissions and improved specific fuel consumption can be met by incorporating heat exchangers into gas turbines. Relevant researches in such areas as the design of a heat exchanger matrix, materials selection, manufacturing technology, and optimization by a variety of researchers have been reviewed in this paper. Based on results reported in previous studies, potential heat exchanger designs for an aero gas turbine recuperator, intercooler, and cooling-air cooler are suggested.

Vector magnetometer design study: Analysis of a triaxial fluxgate sensor design demonstrates that all MAGSAT Vector Magnetometer specifications can be met

NASA Technical Reports Server (NTRS)

Adams, D. F.; Hartmann, U. G.; Lazarow, L. L.; Maloy, J. O.; Mohler, G. W.

1976-01-01

The design of the vector magnetometer selected for analysis is capable of exceeding the required accuracy of 5 gamma per vector field component. The principal elements that assure this performance level are very low power dissipation triaxial feedback coils surrounding ring core flux-gates and temperature control of the critical components of two-loop feedback electronics. An analysis of the calibration problem points to the need for improved test facilities.

Active lithium chloride cell for spacecraft power

NASA Technical Reports Server (NTRS)

Fleischmann, C. W.; Horning, R. J.

1988-01-01

An active thionyl chloride high rate battery is under development for spacecraft operations. It is a 540kC (150 Ah) battery capable of pulses up to 75A. This paper describes the design and initial test data on a 'state-of-the-art' cell that has been selected to be the baseline for the prototype cell for that battery. Initial data indicate that the specification can be met with fresh cells. Data for stored cells and additional environmental test data are in the process of being developed.

Executive dysfunction assessed by Clock-Drawing Test in older non-demented subjects with metabolic syndrome is not mediated by white matter lesions.

PubMed

Viscogliosi, Giovanni; Chiriac, Iulia Maria; Andreozzi, Paola; Ettorre, Evaristo

2015-10-01

Metabolic syndrome (MetS) has been associated with greater occurrence of white matter hyperintensities (WMH). It remains uncertain whether MetS as a construct is associated with poorer cognitive performances. This study explores whether MetS is associated with poorer performances in global and domain-specific cognitive tests in older non-demented subjects independently of its individual components, WMH severity and other variables. MetS was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III definition. Brain magnetic resonance studies (1.5T) were performed. Deep and periventricular WMH were graded using the Fazekas scale. Subjects underwent the Mini-Mental State Examination, the Babcock Short Story Recall test and the Clock-Drawing Test (CDT). Eighty community-dwellers aged 67-91 years were studied. Subjects with MetS (n = 35) had more severe WMH, and poorer performances on the CDT (P = 0.003) and the Babcock Short Story Recall test (P = 0.027). After multiple adjustment, MetS was inversely associated with CDT scores (B = -1.285; 95% confidence interval = -1.996--0.575; P = 0.001) but not with episodic memory. Results were not affected by WMH severity. Interestingly, none of the individual components of MetS predicted poorer cognitive performances. Impairment in executive functions assessed by CDT may represent an early and specific sign of cognitive decline in older individuals with MetS. Future longitudinal studies are needed to better establish the predictive role of MetS on dementia and to demonstrate the possibility of dementia prevention by targeting MetS. © 2015 The Authors. Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology.

The co-occurrence of anemia and cardiometabolic disease risk demonstrates sex-specific sociodemographic patterning in an urbanizing rural region of southern India.

PubMed

Jones, A D; Hayter, A K M; Baker, C P; Prabhakaran, P; Gupta, V; Kulkarni, B; Smith, G D; Ben-Shlomo, Y; Krishna, K V R; Kumar, P U; Kinra, S

2016-03-01

To determine the extent and sociodemographic determinants of anemia, overweight, metabolic syndrome (MetS) and the co-occurrence of anemia with cardiometabolic disease risk factors among a cohort of Indian adults. Cross-sectional survey of adult men (n=3322) and nonpregnant women (n=2895) aged 18 years and older from the third wave of the Andhra Pradesh Children and Parents Study that assessed anemia, overweight based on body mass index, and prevalence of MetS based on abdominal obesity, hypertension and blood lipid and fasting glucose measures. We examined associations of education, wealth and urbanicity with these outcomes and their co-occurrence. The prevalence of anemia and overweight was 40% and 29% among women, respectively, and 10% and 25% among men (P<0.001), respectively, whereas the prevalence of MetS was the same across sexes (15%; P=0.55). The prevalence of concurrent anemia and overweight (9%), and anemia and MetS (4.5%) was highest among women. Household wealth was positively associated with overweight and MetS across sexes (P<0.05). Independent of household wealth, higher education was positively correlated with MetS among men (odds ratio (95% confidence interval): MetS: 1.4 (0.99, 2.0)) and negatively correlated with MetS among women (MetS: 0.54 (0.29, 0.99)). Similar sex-specific associations were observed for the co-occurrence of anemia with overweight and MetS. Women in this region of India may be particularly vulnerable to co-occurring anemia and cardiometabolic risk, and associated adverse health outcomes as the nutrition transition advances in India.

The co-occurrence of anemia and cardiometabolic disease risk demonstrates sex-specific sociodemographic patterning in an urbanizing rural region of southern India

PubMed Central

Jones, Andrew D.; Hayter, Arabella K.M.; Baker, Chris P.; Prabhakaran, Poornima; Gupta, Vipin; Kulkarni, Bharati; Davey Smith, George; Ben-Shlomo, Yoav; Radha Krishna, K.V.; Kumar, P. Uday; Kinra, Sanjay

2015-01-01

Background/Objectives To determine the extent and sociodemographic determinants of anemia, overweight, metabolic syndrome (MetS), and the co-occurrence of anemia with cardiometabolic disease risk factors among a cohort of Indian adults. Subject/Methods Cross-sectional survey of adult men (n=3,322) and non-pregnant women (n=2,895) aged 18 y and older from the third wave of the Andhra Pradesh Children and Parents Study that assessed anemia, overweight based on Body Mass Index, and prevalence of MetS based on abdominal obesity, hypertension, and blood lipid and fasting glucose measures. We examined associations of education, wealth and urbanicity with these outcomes and their co-occurrence. Results The prevalence of anemia and overweight was 40% and 29% among women, respectively, and 10% and 25% among men (P<0.001), respectively, while the prevalence of MetS was the same across sexes (15%) (P=0.55). The prevalence of concurrent anemia and overweight (9%), and anemia and MetS (4.5%) was highest among women. Household wealth was positively associated with overweight and MetS across sexes (P<0.05). Independent of household wealth, higher education was positively correlated with MetS among men (OR (95% CI): MetS: 1.4 (0.99, 2.0)) and negatively correlated with MetS among women (MetS: 0.54 (0.29, 0.99)). Similar sex-specific associations were observed for the co-occurrence of anemia with overweight and MetS. Conclusion Women in this region of India may be particularly vulnerable to co-occurring anemia and cardiometabolic risk, and associated adverse health outcomes as the nutrition transition advances in India. PMID:26508461

GGA3 Functions as a Switch to Promote Met Receptor Recycling, Essential for Sustained ERK and Cell Migration

PubMed Central

Parachoniak, Christine Anna; Luo, Yi; Abella, Jasmine Vanessa; Keen, James H.; Park, Morag

2011-01-01

Summary Cells are dependent on correct sorting of activated receptor tyrosine kinases (RTKs) for the outcome of growth factor signaling. Upon activation, RTKs are coupled through the endocytic machinery for degradation, or recycled to the cell surface. However, the molecular mechanisms governing RTK recycling are poorly understood. Here, we show that Golgi-localized gamma-ear containing Arf-binding protein 3 (GGA3) interacts selectively with the Met/Hepatocyte Growth Factor RTK when stimulated, to sort it for recycling in association with “gyrating”-clathrin. GGA3 loss abrogates Met recycling from a Rab4 endosomal subdomain, resulting in pronounced trafficking of Met towards degradation. Decreased Met recycling attenuates ERK activation and cell migration. Met recycling, sustained ERK activation and migration require interaction of GGA3 with Arf6 and an unexpected association with the Crk adaptor. The data show that GGA3 defines an active recycling pathway and support a broader role for GGA3-mediated cargo selection in targeting receptors destined for recycling. PMID:21664574

Improving the sensitivity and specificity of a bioanalytical assay for the measurement of certolizumab pegol.

PubMed

Smeraglia, John; Silva, John-Paul; Jones, Kieran

2017-08-01

In order to evaluate placental transfer of certolizumab pegol (CZP), a more sensitive and selective bioanalytical assay was required to accurately measure low CZP concentrations in infant and umbilical cord blood. Results & methodology: A new electrochemiluminescence immunoassay was developed to measure CZP levels in human plasma. Validation experiments demonstrated improved selectivity (no matrix interference observed) and a detection range of 0.032-5.0 μg/ml. Accuracy and precision met acceptance criteria (mean total error ≤20.8%). Dilution linearity and sample stability were acceptable and sufficient to support the method. The electrochemiluminescence immunoassay was validated for measuring low CZP concentrations in human plasma. The method demonstrated a more than tenfold increase in sensitivity compared with previous assays, and improved selectivity for intact CZP.

Identification of auxotrophic mutants of the yeast Kluyveromyces marxianus by non-homologous end joining-mediated integrative transformation with genes from Saccharomyces cerevisiae.

PubMed

Yarimizu, Tohru; Nonklang, Sanom; Nakamura, Junpei; Tokuda, Shuya; Nakagawa, Takaaki; Lorreungsil, Sasithorn; Sutthikhumpha, Surasit; Pukahuta, Charida; Kitagawa, Takao; Nakamura, Mikiko; Cha-Aim, Kamonchai; Limtong, Savitree; Hoshida, Hisashi; Akada, Rinji

2013-12-01

The isolation and application of auxotrophic mutants for gene manipulations, such as genetic transformation, mating selection and tetrad analysis, form the basis of yeast genetics. For the development of these genetic methods in the thermotolerant fermentative yeast Kluyveromyces marxianus, we isolated a series of auxotrophic mutants with defects in amino acid or nucleic acid metabolism. To identify the mutated genes, linear DNA fragments of nutrient biosynthetic pathway genes were amplified from Saccharomyces cerevisiae chromosomal DNA and used to directly transform the K. marxianus auxotrophic mutants by random integration into chromosomes through non-homologous end joining (NHEJ). The appearance of transformant colonies indicated that the specific S. cerevisiae gene complemented the K. marxianus mutant. Using this interspecific complementation approach with linear PCR-amplified DNA, we identified auxotrophic mutations of ADE2, ADE5,7, ADE6, HIS2, HIS3, HIS4, HIS5, HIS6, HIS7, LYS1, LYS2, LYS4, LYS9, LEU1, LEU2, MET2, MET6, MET17, TRP3, TRP4 and TRP5 without the labour-intensive requirement of plasmid construction. Mating, sporulation and tetrad analysis techniques for K. marxianus were also established. With the identified auxotrophic mutant strains and S. cerevisiae genes as selective markers, NHEJ-mediated integrative transformation with PCR-amplified DNA is an attractive system for facilitating genetic analyses in the yeast K. marxianus. Copyright © 2013 John Wiley & Sons, Ltd.

Radioligand binding, autoradiographic and functional studies demonstrate tachykinin NK-2 receptors in dog urinary bladder.

PubMed

Mussap, C J; Stamatakos, C; Burcher, E

1996-10-01

Tachykinin receptors in the dog bladder were characterized using radioligand binding, functional and autoradiographic techniques. In detrusor muscle homogenates, specific binding of [125l]iodohistidyl neurokinin A (INKA) and [125l]Bolton Hunter eledoisin was reversible, saturable and, to a single class of sites of Kd, 3,6 and 27 nM, respectively. No specific binding of [125l]Bolton Hunter[Sar9, Met (O2)11] substance P occurred. INKA binding was reduced by the peptidase inhibitor bacitracin. The rank potency order of agonists competing for binding of both radioligands indicated interaction at NK-2 sites. NK-2-selective antagonists also competed for INKA binding, with SR 48968, GR 94800, MDL 29913 and the selective agonist [Lys5, MeLeu9, Nle10]-NKA(4-10) showing biphasic binding profiles. Autoradiographic studies revealed specific binding of INKA and [125l]Bolton Hunter eledoisin over detrusor muscle and small arteries. [125l]Bolton Hunter [Sar9, Met (O2)11] SP labeled the intima of arteries and arterioles, but not the detrusor muscle. Tachykinins contracted detrusor muscle strips, with potency order at the carbachol EC15 NKA = kassinin > [Lys5, MeLeu9, Nle10]-NKA(4-10) = neuropeptide gamma = neuropeptide K = NKB > > MDL 28564, with [Sar9, Met(O2)11]-SP ineffective. Shallow concentration-response curves, variable efficacies and inhibition by atropine and mepyramine suggest that other mechanisms may influence contractile responses. Responses to [Lys5, MeLeu9, Nle10]-NKA(4-10) were inhibited competitively by MDL 29913 and MEN 10207 (pA2 values: 6.4 and 5.3, respectively). Antagonism by SR 48968 and GR 94800 was noncompetitive (both pK8 values 8.9). In summary, NK-2-preferring ligands showed superior potency as both binding competitors and contractile agonists, demonstrating that NK-2 receptors mediate detrusor muscle contraction, similar to the human detrusor. Tachykinins may play important roles in the micturition reflex and in regulating detrusor muscle blood flow in the dog.

Sufentanil, Morphine, Met-enkephalin, and κ-Agonist (U-50,488H) Inhibit Substance P Release from Primary Sensory-Neurons: A Model for Presynaptic Spinal Opioid Actions

PubMed Central

Chang, H. Ming; Berde, Charles B.; Holz, George G.; Steward, Grieg F.; Kream, Richard M.

2010-01-01

An in vitro model system for analysis of presynaptic inhibitory actions of spinal opioids has been applied. Embryonic sensory neurons derived from chick dorsal root ganglia were grown in primary cell culture, and the release of substance P was evoked by electrical field stimulation during exposure to drugs with well-demonstrated affinity for opioid receptors. This allowed a pharmacologic characterization of the inhibitory actions of specific opioid agonists on the release of substance P as measured by radioimmunoassay (RIA). Sufentanil (0.5 µm), a high affinity µ receptor agonist, U-50,488H (25 µm), a selective κ receptor agonist, and morphine (10 µm), an agonist with high affinity for µ and δ receptors, inhibited the evoked release of substance P by approximately 60%, 40%, and 50%, respectively. For sufentanil the response was demonstrated to be dose-dependent. As is the case for its analgesic action in vivo, morphine was approximately 50-fold less potent than sufentanil on a molar basis in this assay. The actions of sufentanil, U-50-488H and morphine were mimicked by the endogenous opioid peptide met-enkephalin, and its stable synthetic analog D-ala2-met5-enkephalinamide (DAME). Naloxone (25 µm), an opioid receptor antagonist, blocked the inhibitory action of sufentanil (0.5 µm), morphine (5 µm), and DAME (5 µm), but not U-50,488H (10 µm). The action of U-50,488H was partially blocked by the antagonist naltrexone (25 µm). Stereo-selectivity of agonist action was confirmed by the failure of dextrorphan (50 µm), an inactive opioid isomer, to inhibit the release of substance P. Actions mediated by specific opioid receptors were thus demonstrated by high affinity responses to agonists, blockade of agonist responses by opioid antagonists, and stereoselectivity. These findings suggest that in the spinal cord presynaptic inhibition of evoked substance P release is mediated by µ, K and δ opioid receptors located on primary sensory nerve terminals. Activation of these receptors may explain, at least in part, the spinal analgesic actions of specific opioid agonists. PMID:2467589

The effect of heritability and host genetics on the gut microbiota and metabolic syndrome.

PubMed

Lim, Mi Young; You, Hyun Ju; Yoon, Hyo Shin; Kwon, Bomi; Lee, Jae Yoon; Lee, Sunghee; Song, Yun-Mi; Lee, Kayoung; Sung, Joohon; Ko, GwangPyo

2017-06-01

Metabolic syndrome (MetS) arises from complex interactions between host genetic and environmental factors. Although it is now widely accepted that the gut microbiota plays a crucial role in host metabolism, current knowledge on the effect of host genetics on specific gut microbes related to MetS status remains limited. Here, we investigated the links among host genetic factors, gut microbiota and MetS in humans. We characterised the gut microbial community composition of 655 monozygotic (n=306) and dizygotic (n=74) twins and their families (n=275), of which approximately 18% (121 individuals) had MetS. We evaluated the association of MetS status with the gut microbiota and estimated the heritability of each taxon. For the MetS-related and heritable taxa, we further investigated their associations with the apolipoprotein A-V gene ( APOA5 ) single nucleotide polymorphism (SNP) rs651821, which is known to be associated with triglyceride levels and MetS. Individuals with MetS had a lower gut microbiota diversity than healthy individuals. The abundances of several taxa were associated with MetS status; Sutterella , Methanobrevibacter and Lactobacillus were enriched in the MetS group, whereas Akkermansia , Odoribacter and Bifidobacterium were enriched in the healthy group. Among the taxa associated with MetS status, the phylum Actinobacteria, to which Bifidobacterium belongs, had the highest heritability (45.7%). Even after adjustment for MetS status, reduced abundances of Actinobacteria and Bifidobacterium were significantly linked to the minor allele at the APOA5 SNP rs651821. Our results suggest that an altered microbiota composition mediated by a specific host genotype can contribute to the development of MetS. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Health-related quality of life assessment among patients with inflammatory bowel diseases after surgery – review

PubMed Central

Formanowicz, Dorota; Gmerek, Łukasz; Krokowicz, Piotr

2016-01-01

Aim of the work was to review systematically the published literature addressing whether quality of life (QoL) and health-related QoL (HRQoL) are influenced by surgery among patients with inflammatory bowel disease (IBD). Electronic databases and published articles were searched to identify relevant studies published in the years 1990–2015. Then, a multistep selection was undertaken to identify articles that met specific selection criteria, such us specific key-words (IBD, HRQoL, ulcerative colitis (UC), Crohn’s disease (CD), and surgery), and the population was assessed (studies concerning patients < 18 years old were excluded). The review included 27 studies that were evaluated in the context of the influence of surgery on QoL and HRQoL. Concluding, with the increase in the incidence of IBD, monitoring of QoL is an important indicator of the health effects at each stage of the surgical treatment. PMID:28337230

Shape optimization of disc-type flywheels

NASA Technical Reports Server (NTRS)

Nizza, R. S.

1976-01-01

Techniques were developed for presenting an analytical and graphical means for selecting an optimum flywheel system design, based on system requirements, geometric constraints, and weight limitations. The techniques for creating an analytical solution are formulated from energy and structural principals. The resulting flywheel design relates stress and strain pattern distribution, operating speeds, geometry, and specific energy levels. The design techniques incorporate the lowest stressed flywheel for any particular application and achieve the highest specific energy per unit flywheel weight possible. Stress and strain contour mapping and sectional profile plotting reflect the results of the structural behavior manifested under rotating conditions. This approach toward flywheel design is applicable to any metal flywheel, and permits the selection of the flywheel design to be based solely on the criteria of the system requirements that must be met, those that must be optimized, and those system parameters that may be permitted to vary.

Development of a LC-MS/MS method for simultaneous determination of metoprolol and its metabolites, α-hydroxymetoprolol and O-desmethylmetoprolol, in rat plasma: application to the herb-drug interaction study of metoprolol and breviscapine.

PubMed

Rao, Zhi; Ma, Yan-rong; Qin, Hong-yan; Wang, Ya-feng; Wei, Yu-hui; Zhou, Yan; Zhang, Guo-qiang; Wang, Xing-dong; Wu, Xin-an

2015-09-01

A simple, specific and sensitive LC-MS/MS method was developed and validated for the simultaneous determination of metoprolol (MET), α-hydroxymetoprolol (HMT) and O-desmethylmetoprolol (DMT) in rat plasma. The plasma samples were prepared by protein precipitation, then the separation of the analytes was performed on an Agilent HC-C18 column (4.6 × 250 mm, 5 µm) at a flow rate of 1.0 mL/min, and post-column splitting (1:4) was used to give optimal interface flow rates (0.2 mL/min) for MS detection; the total run time was 8.5 min. Mass spectrometric detection was achieved using a triple-quadrupole mass spectrometer equipped with an electrospray source interface in positive ionization mode. The method was fully validated in terms of selectivity, linearity, accuracy, precision, stability, matrix effect and recovery over a concentration range of 3.42-7000 ng/mL for MET, 2.05-4200 ng/mL for HMT and 1.95-4000 ng/mL for DMT. The analytical method was successfully applied to herb-drug interaction study of MET and breviscapine after administration of breviscapine (12.5 mg/kg) and MET (40 mg/kg). The results suggested that breviscapine have negligible effect on pharmacokinetics of MET in rats; the information may be beneficial for the application of breviscapine in combination with MET in clinical therapy. Copyright © 2015 John Wiley & Sons, Ltd.

The Pleiotropic MET Receptor Network: Circuit Development and the Neural-Medical Interface of Autism

PubMed Central

Eagleson, Kathie L.; Xie, Zhihui; Levitt, Pat

2016-01-01

People with autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDDs) are behaviorally and medically heterogeneous. The combination of polygenicity and gene pleiotropy - the influence of one gene on distinct phenotypes - raises questions of how specific genes and their protein products interact to contribute to NDDs. A preponderance of evidence supports developmental and pathophysiological roles for the MET receptor tyrosine kinase, a multi-functional receptor that mediates distinct biological responses depending upon cell context. MET influences neuron architecture and synapse maturation in the forebrain, and regulates homeostasis in gastrointestinal and immune systems, both commonly disrupted in NDDs. Peak expression of synapse-enriched MET is conserved across rodent and primate forebrain, yet regional differences in primate neocortex are pronounced, with enrichment in circuits that participate in social information processing. A functional risk allele in the MET promoter, enriched in subgroups of children with ASD, reduces transcription and disrupts socially-relevant neural circuits structurally and functionally. In mice, circuit-specific deletion of Met causes distinct atypical behaviors. MET activation increases dendritic complexity and nascent synapse number, but synapse maturation requires reductions in MET. MET mediates its specific biological effects through different intracellular signaling pathways, and has a complex protein interactome that is enriched in ASD and other NDD candidates. The interactome is co-regulated in developing human neocortex. We suggest that a gene as pleiotropic and highly regulated as MET, together with its interactome, is biologically relevant in normal and pathophysiological contexts, impacting central and peripheral phenotypes that contribute to NDD risk and clinical symptoms. PMID:27837921

Gender- and Race-Specific Metabolic Score and Cardiovascular Disease Mortality in Adults: A Structural Equation Modeling Approach—United States, 1988–2006

PubMed Central

Mercado, Carla I.; Yang, Quanhe; Ford, Earl S.; Gregg, Edward; Valderrama, Amy L.

2017-01-01

Objective Consider all metabolic syndrome (MetS) components [systolic (SBP) and diastolic (DBP) blood pressures, waist circumference, HDL cholesterol, triglycerides (TG), and fasting glucose] and gender/race differential risk when assessing cardiovascular disease (CVD) risk. Methods We estimated a gender- and race-specific continuous MetS score using structural equation modeling and tested its association with CVD mortality using data from National Health and Nutrition Examination Survey III linked with the National Death Index. Cox proportional hazard regression tested the association adjusted for sociodemographic and behavior characteristics. Results For men, continuous MetS components associated with CVD mortality were SBP (hazard ratio =1.50, 95% confidence interval =1.14–1.96), DBP (1.48, 1.16–1.90), and TG (1.15, 1.12–1.16). In women, SBP (1.44, 1.27–1.63) and DBP (1.24, 1.02–1.51) were associated with CVD mortality. MetS score was not significantly associated with CVD mortality in men; but significant associations were found for all women (1.34, 1.06–1.68), non-Hispanic white women (1.29, 1.01–1.64), non-Hispanic black women (2.03, 1.12–3.69), and Mexican-American women (3.57, 2.21–5.76). Goodness-of-fit and concordance were overall better for models with the MetS score than MetS (yes/no). Conclusions When assessing CVD mortality risk, MetS score provided additional information than MetS (yes/no). PMID:26308480

Effect of oxidation of the non-catalytic β-propeller domain on the substrate specificity of prolyl oligopeptidase from Pleurotus eryngii.

PubMed

Tokai, Shota; Bito, Tomohiro; Shimizu, Katsuhiko; Arima, Jiro

2017-05-27

Enzymes belonging to the S9 family of prolyl oligopeptidases are of interest because of their pharmacological importance and have a non-catalytic β-propeller domain. In this study, we found that the oxidation of Met203, which lies on surface of the β-propeller domain, leads to change in the substrate specificity of eryngase, an enzyme from Pleurotus eryngii and a member of the S9 family of prolyl oligopeptidases. The activity of eryngase for L-Phe-p-nitroanilide was maintained following hydrogen peroxide treatment but was dramatically reduced for other p-nitroanilide substrates. MALDI-TOF MS analysis using tryptic peptides of eryngase indicated that the change in substrate specificity was triggered by oxidizing Met203 to methionine sulfoxide. In addition, mutations of Met203 to smaller residues provided specificities similar to those observed following oxidation of the wild-type enzyme. Substitution of Met203 with Phe significantly decreased activity, indicating that Met203 may be involved in substrate gating. Copyright © 2017 Elsevier Inc. All rights reserved.

Genomics of a Metamorphic Timing QTL: met1 Maps to a Unique Genomic Position and Regulates Morph and Species-Specific Patterns of Brain Transcription

PubMed Central

Page, Robert B.; Boley, Meredith A.; Kump, David K.; Voss, Stephen R.

2013-01-01

Very little is known about genetic factors that regulate life history transitions during ontogeny. Closely related tiger salamanders (Ambystoma species complex) show extreme variation in metamorphic timing, with some species foregoing metamorphosis altogether, an adaptive trait called paedomorphosis. Previous studies identified a major effect quantitative trait locus (met1) for metamorphic timing and expression of paedomorphosis in hybrid crosses between the biphasic Eastern tiger salamander (Ambystoma tigrinum tigrinum) and the paedomorphic Mexican axolotl (Ambystoma mexicanum). We used existing hybrid mapping panels and a newly created hybrid cross to map the met1 genomic region and determine the effect of met1 on larval growth, metamorphic timing, and gene expression in the brain. We show that met1 maps to the position of a urodele-specific chromosome rearrangement on linkage group 2 that uniquely brought functionally associated genes into linkage. Furthermore, we found that more than 200 genes were differentially expressed during larval development as a function of met1 genotype. This list of differentially expressed genes is enriched for proteins that function in the mitochondria, providing evidence of a link between met1, thyroid hormone signaling, and mitochondrial energetics associated with metamorphosis. Finally, we found that met1 significantly affected metamorphic timing in hybrids, but not early larval growth rate. Collectively, our results show that met1 regulates species and morph-specific patterns of brain transcription and life history variation. PMID:23946331

Interactive effects of the COMT gene and training on individual differences in supervisory control of unmanned vehicles.

PubMed

Parasuraman, Raja; Kidwell, Brian; Olmstead, Ryan; Lin, Ming-Kuan; Jankord, Ryan; Greenwood, Pamela

2014-06-01

We examined whether a gene known to influence dopamine availability in the prefrontal cortex is associated with individual differences in learning a supervisory control task. Methods are needed for selection and training of human operators who can effectively supervise multiple unmanned vehicles (UVs). Compared to the valine (Val) allele, the methionine (Met) allele of the COMT gene has been linked to superior executive function, but it is not known whether it is associated with training-related effects in multi-UV supervisory control performance. Ninety-nine healthy adults were genotyped for the COMT Val158Met single nucleotide polymorphism (rs4680) and divided into Met/Met, Val/Met, and Val/Val groups. Participants supervised six UVs in an air defense mission requiring them to attack incoming enemy aircraft and protect a no-fly zone from intruders in conditions of low and high task load (numbers of enemy aircraft). Training effects were examined across four blocks of trials in each task load condition. Compared to the Val/Met and Val/Val groups, Met/Met individuals exhibited a greater increase in enemy targets destroyed and greater reduction in enemy red zone incursions across training blocks. Individuals with the COMT Met/Met genotype can acquire skill in executive function tasks, such as multi-UV supervisory control, to a higher level and/or faster than other genotype groups. Potential applications of this research include the development of individualized training methods for operators of multi-UV systems and selecting personnel for complex supervisory control tasks.

Proteinase-activated receptor 2 (PAR(2)) in cholangiocarcinoma (CCA) cells: effects on signaling and cellular level.

PubMed

Kaufmann, Roland; Hascher, Alexander; Mussbach, Franziska; Henklein, Petra; Katenkamp, Kathrin; Westermann, Martin; Settmacher, Utz

2012-12-01

In this study, we demonstrate functional expression of the proteinase-activated receptor 2 (PAR(2)), a member of a G-protein receptor subfamily in primary cholangiocarcinoma (PCCA) cell cultures. Treatment of PCCA cells with the serine proteinase trypsin and the PAR(2)-selective activating peptide, furoyl-LIGRLO-NH(2), increased migration across a collagen membrane barrier. This effect was inhibited by a PAR(2)-selective pepducin antagonist peptide (P2pal-18S) and it was also blocked with the Met receptor tyrosine kinase (Met) inhibitors SU 11274 and PHA 665752, the MAPKinase inhibitors PD 98059 and SL 327, and the Stat3 inhibitor Stattic. The involvement of Met, p42/p44 MAPKinases and Stat3 in PAR(2)-mediated PCCA cell signaling was further supported by the findings that trypsin and the PAR(2)-selective agonist peptide, 2-furoyl-LIGRLO-NH(2), stimulated activating phosphorylation of these signaling molecules in cholangiocarcinoma cells. With our results, we provide a novel signal transduction module in cholangiocarcinoma cell migration involving PAR(2)-driven activation of Met, p42/p44 MAPKinases and Stat3.

Specific features of colorectal cancer in patients with metabolic syndrome: a matched case-control analysis of 772 patients.

PubMed

Zarzavadjian Le Bian, Alban; Denet, Christine; Tabchouri, Nicolas; Donatelli, Gianfranco; Wind, Philippe; Louvet, Christophe; Bennamoun, Mostefa; Christidis, Christos; Perniceni, Thierry; Fuks, David; Gayet, Brice

2018-06-01

Although association between colorectal cancer (CRC) and metabolic syndrome (MetS) is established, specific features of CRC arising in patients presenting with MetS have not been clearly identified. All patients who underwent colectomy for CRC from January 2005 to December 2014 at Institut Mutualiste Montsouris were identified from a prospectively collected database and characteristics were compared in the entire population and in a 1:2 matched case-control analysis [variables on which matching was performed were CRC localization (right- or left-sided) and AJCC stage (0 to IV)]. Out of the 772 identified patients, 98 (12.7%) presented with MetS. Entire population analysis revealed that CRC associated with MetS was more frequent in men (71.4 vs. 47.8%, p < 0.001), more often right-sided (71.4 vs. 50.4%, p < 0.001) and presented with less synchronous liver metastasis (4.1 vs. 8.7%, p = 0.002). Case-control analysis confirmed the gender association (p < 0.001) and showed HNPCC (p < 0.001) and history family of CRC (p = 0.010) to be significantly more frequent in Non-MetS patients. CRC associated with MetS is more frequent in men, more often right-sided, and presents with fewer synchronous metastasis. Further investigations should be designed in order to confirm these results and to enhance our knowledge of carcinogenesis related to MetS.

MeT-DB V2.0: elucidating context-specific functions of N6-methyl-adenosine methyltranscriptome

PubMed Central

Liu, Hui; Wang, Huaizhi; Wei, Zhen; Zhang, Songyao; Hua, Gang; Zhang, Shao-Wu; Zhang, Lin; Gao, Shou-Jiang

2018-01-01

Abstract Methyltranscriptome is an exciting new area that studies the mechanisms and functions of methylation in transcripts. A knowledge base with the systematic collection and curation of context specific transcriptome-wide methylations is critical for elucidating their biological functions as well as for developing bioinformatics tools. Since its inception in 2014, the Met-DB (Liu, H., Flores, M.A., Meng, J., Zhang, L., Zhao, X., Rao, M.K., Chen, Y. and Huang, Y. (2015) MeT-DB: a database of transcriptome methylation in mammalian cells. Nucleic Acids Res., 43, D197–D203), has become an important resource for methyltranscriptome, especially in the N6-methyl-adenosine (m6A) research community. Here, we report Met-DB v2.0, the significantly improved second version of Met-DB, which is entirely redesigned to focus more on elucidating context-specific m6A functions. Met-DB v2.0 has a major increase in context-specific m6A peaks and single-base sites predicted from 185 samples for 7 species from 26 independent studies. Moreover, it is also integrated with a new database for targets of m6A readers, erasers and writers and expanded with more collections of functional data. The redesigned Met-DB v2.0 web interface and genome browser provide more friendly, powerful, and informative ways to query and visualize the data. More importantly, MeT-DB v2.0 offers for the first time a series of tools specifically designed for understanding m6A functions. Met-DB V2.0 will be a valuable resource for m6A methyltranscriptome research. The Met-DB V2.0 database is available at http://compgenomics.utsa.edu/MeTDB/ and http://www.xjtlu.edu.cn/metdb2. PMID:29126312

The relationship between glucose metabolism, metabolic syndrome, and bone-specific alkaline phosphatase: a structural equation modeling approach.

PubMed

Cheung, Ching-Lung; Tan, Kathryn C B; Lam, Karen S L; Cheung, Bernard M Y

2013-09-01

Serum alkaline phosphatase plays a role in vascular calcification. It is found in various tissues, whereas bone-specific alkaline phosphatase (BAP) more specifically reflects mineral metabolism. The relationship of serum alkaline phosphatase (total and bone-specific) with diabetes and metabolic syndrome (MetS), 2 major risk factors of vascular calcification, is largely unknown. We aimed to investigate the relationships between glucose metabolism, components of the MetS, and alkaline phosphatase. This was a cross-sectional study of a nationally representative sample of the U.S. population in 1999 through 2004. Participants were 3773 nondiabetic participants of the National Health and Nutrition Examination Survey 1999-2004. We measured serum BAP and total alkaline phosphatase. In multivariable linear regression, updated homeostasis model assessment (HOMA2) for insulin resistance (β = 0.068), HOMA2 for β-cell function (β = 0.081), insulin (β = 0.065), mean arterial pressure (β = 0.15), and high-density lipoprotein (HDL)-cholesterol (β = 0.209) were positively associated with BAP, whereas HOMA2 for insulin sensitivity (β = -0.065) was negatively associated with BAP. On the other hand, only mean arterial pressure and HDL-cholesterol were significantly associated with total alkaline phosphatase. Moreover, a structural equation model revealed that hypertension, low HDL, and insulin resistance had significant direct effects on serum BAP levels, whereas obesity and inflammation might have indirect effects on serum BAP levels. The overall model showed very good fit to the data (comparative fit index = 0.995, root mean square error of approximation = 0.037, and standardized root mean square residual = 0.006). Glucose metabolism and MetS are significantly related to serum BAP levels. How BAP mediates vascular calcification in diabetes and MetS warrants further studies.

LAT1 targeted delivery of methionine based imaging probe derived from M(III) metal ions for early diagnosis of proliferating tumours using molecular imaging modalities.

PubMed

Hazari, Puja Panwar; Prakash, Surbhi; Meena, Virendra K; Jaswal, Ambika; Khurana, Harleen; Mishra, Surabhi Kirti; Bhonsle, Hemanth Kumar; Singh, Lokendra; Mishra, Anil K

2015-01-01

We investigated the potential of DTPA-bis(Methionine), a target specific amino acid based probe for detection of L-type amino acid transporters (LAT1) known to over express in proliferating tumours using multimodality imaging. The ligand, DTPA-bis(Met) was readily converted to lanthanide complexes and was found capable of targeting cancer cells using multimodality imaging. DTPA-bis(Met) complexes were synthesized and characterized by mass spectroscopy. MR longitudinal relaxivity, r₁ = 4.067 ± 0.31 mM⁻¹s⁻¹ and transverse relaxivity, r₂ = 8.61 ± 0.07 mM⁻¹s⁻¹ of Gd(III)-DTPA-bis(Met) were observed at pH 7.4 at 7 T. Bright, localized fluorescence of Eu(III)-DTPA-bis(Met) was observed with standard microscopy and displacement studies indicated ligand functionality. K(D) value determined for Eu(III)-DTPA-bis(Met) on U-87 MG cells was found to be 17.3 pM and showed appreciable fluorescence within the cells. Radio HPLC showed a radiochemical purity more than 95% (specific activity = 400-500 MBq/μmol, labelling efficiency 78 %) for ⁶⁸Ga(III)-DTPA-bis(Met). Pre-treatment of xenografted U-87 MG athymic mice with ⁶⁸Ga(III)-DTPA-bis(Met) following unlabelled L-methionine administration reduced tumour uptake by 10-folds in Micro PET. These data support the specific binding of ⁶⁸Ga(III)-DTPA-bis(Met) to the LAT1 transporter. To summarize, this agent possesses high stability in biological environment and exhibits effective interaction with its LAT1 transporters giving high accumulation in tumour area, excellent tumour/non-tumour ratio and low non-specific retention in vivo.

The natural logarithm of zinc-α2-glycoprotein/HOMA-IR is a better predictor of insulin sensitivity than the product of triglycerides and glucose and the other lipid ratios.

PubMed

Qu, Chunmei; Zhou, Xiaoxin; Yang, Gangyi; Li, Ling; Liu, Hua; Liang, Zerong

2016-03-01

The euglycemic-hyperinsulinemic clamp (EHC) is not available in most clinical settings and is costly, time consuming and invasive, and requires trained staff. Therefore, an accessible and inexpensive test to identify insulin resistance (IR) is needed. The aim of this study is to assess whether zinc-α2-glycoprotein (ZAG) index [Ln ZAG/homeostasis model assessment of IR (HOMA-IR)] is a better surrogate index for estimating IR or metabolic syndrome (MetS) compared with other surrogate indices. We performed a population-based cross-sectional study. Two hundred healthy subjects, 102 polycystic ovary syndrome (PCOS) patients, 97 newly diagnosed type 2 diabetes mellitus (nT2DM) and 84 impaired glucose tolerance (IGT) subjects were enrolled. The EHC was performed to identify IR. Circulating ZAG and adiponectin levels were determined by ELISA. The ZAG index was significantly lower in participants with IR including IGT, nT2DM and PCOS than in those without IR. In addition, subjects with MetS had lower ZAG indices and higher the product of fasting triglycerides and glucose (TyG) indices than those without MetS. The ZAG index showed a significantly stronger association with M values than the other surrogate indices, whereas the TyG index showed a stronger association with MetS. The optimal cutoff value of the ZAG index for detection of IR was 2.97 with a sensitivity of 88% and a specificity of 91%, whereas the optimal cutoff value of TyG index for detection of MetS was 4.90 with a sensitivity of 82% and a specificity of 86%. The ZAG index is a better marker than the other surrogate indices for identifying IR, whereas the TyG index has high sensitivity and specificity for identifying MetS. Copyright © 2016 Elsevier Ltd. All rights reserved.

Have Clinical Trials Properly Assessed c-Met Inhibitors?

PubMed

Hughes, Veronica S; Siemann, Dietmar W

2018-02-01

The c-Met/HGF pathway is implicated in cancer progression and dissemination. Many inhibitors have been developed to target this pathway. Unfortunately, most trials have failed to demonstrate efficacy. However, clinical trials have not adequately tested the concept of c-Met pathway inhibition due to the lack of appropriate patient selection criteria. Copyright © 2017 Elsevier Inc. All rights reserved.

Gender-specific differences in the incidence of microalbuminuria in metabolic syndrome patients after treatment with fimasartan: The K-MetS study

PubMed Central

Kim, Su-A; Sung, Ki-Chul; Kim, Jang Young

2017-01-01

Background The effect of resolving metabolic syndrome on target organ damage in hypertensive patients is not well described. We evaluated whether treating metabolic syndrome (MetS) with an angiotensin receptor blocker subsequently reduced microalbuminuria in the K-MetS cohort. Methods Among 10,601 total metabolic syndrome patients, 3,250 (52.2% male, 56.2±10.0 years) with sufficient data on five specific metabolic components were included in this study. Patients were divided into four groups based on MetS status at baseline and 3 months. All patients received an angiotensin receptor blocker, fimasartan, for these 3 months; thereafter, treatment was modified at the discretion of each patient’s physician. Microalbuminuria and the albumin/creatine ratio were evaluated as a proxy of organ damage. Results Blood pressure and waist circumference decreased from baseline to 3 months and 1 year. The average albumin/creatinine ratio significantly improved during the first three months of the study from 36.0±147.4 to 21.0±74.9 mg/g (p<0.05) and was persistently high in patients with MetS at baseline and 3 months versus other groups. Women in comparison with men showed significantly lower ACR among patients with newly developed MetS at 3-month. Conclusions Treatment of hypertensive patients for one year with the angiotensin receptor blocker fimasartan significantly reduced the albumin/creatine ratio, irrespective of whether the patient had MetS; however, the albumin/creatinine ratio was significantly higher in patents with persistent or newly developed MetS compared to patients without MetS. Additionally, these findings were more prominent in women than in men. PMID:29261715

Cereal, fruit and vegetable fibre intake and the risk of the metabolic syndrome: a prospective study in the Tehran Lipid and Glucose Study.

PubMed

Hosseinpour-Niazi, S; Mirmiran, P; Mirzaei, S; Azizi, F

2015-06-01

The present study aimed to determine whether total fibre or specific fibre food sources are associated with the incidence of the metabolic syndrome (MetS) after 3 years of follow-up in the Tehran Lipid and Glucose Study. This population-based prospective study, conducted within the framework of the Tehran Lipid and Glucose Study, included 1582 adults, who were aged 19-84 years and free of MetS at baseline. Usual dietary fibre intake was assessed at baseline using a 168-item food frequency questionnaire. Anthropometrics, blood pressure, and fasting blood glucose and lipid profiles were measured at baseline and 3 years later. The MetS was defined according to the definition of the revised Adult treatment Panel III. During the 3-year follow-up, there was 15.2% incidence of MetS. Among sources of dietary fibre, fruit fibre was significantly and inversely associated with the occurrence of MetS, after adjustment for confounding factors, with a 21% lower risk [odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.60-0.97] in the highest tertile of intake compared to the lowest tertile. Subjects in the highest tertile of cereal fibre intake had lower odds of MetS compared to those in the lowest tertile (OR = 0.73, 95% CI = 0.52- 0.97) and this association disappeared after adjustment for confounders. No significant association was found between intakes of vegetables, legumes and nut fibre with the incidence of MetS. Among specific fibre food sources, fruit fibre had a protective effect against the risk of MetS. © 2014 The British Dietetic Association Ltd.

The Pleiotropic MET Receptor Network: Circuit Development and the Neural-Medical Interface of Autism.

PubMed

Eagleson, Kathie L; Xie, Zhihui; Levitt, Pat

2017-03-01

People with autism spectrum disorder and other neurodevelopmental disorders (NDDs) are behaviorally and medically heterogeneous. The combination of polygenicity and gene pleiotropy-the influence of one gene on distinct phenotypes-raises questions of how specific genes and their protein products interact to contribute to NDDs. A preponderance of evidence supports developmental and pathophysiological roles for the MET receptor tyrosine kinase, a multifunctional receptor that mediates distinct biological responses depending upon cell context. MET influences neuron architecture and synapse maturation in the forebrain and regulates homeostasis in gastrointestinal and immune systems, both commonly disrupted in NDDs. Peak expression of synapse-enriched MET is conserved across rodent and primate forebrain, yet regional differences in primate neocortex are pronounced, with enrichment in circuits that participate in social information processing. A functional risk allele in the MET promoter, enriched in subgroups of children with autism spectrum disorder, reduces transcription and disrupts socially relevant neural circuits structurally and functionally. In mice, circuit-specific deletion of Met causes distinct atypical behaviors. MET activation increases dendritic complexity and nascent synapse number, but synapse maturation requires reductions in MET. MET mediates its specific biological effects through different intracellular signaling pathways and has a complex protein interactome that is enriched in autism spectrum disorder and other NDD candidates. The interactome is coregulated in developing human neocortex. We suggest that a gene as pleiotropic and highly regulated as MET, together with its interactome, is biologically relevant in normal and pathophysiological contexts, affecting central and peripheral phenotypes that contribute to NDD risk and clinical symptoms. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Sun protection policies and practices in New Zealand primary schools.

PubMed

Reeder, Anthony I; Jopson, Janet A; Gray, Andrew

2012-02-10

For schools with primary age students, to report the percentages meeting specific requirements of the New Zealand SunSmart Schools Accreditation Programme (SSAP). Schools were randomly selected, within geographic regions, from the Ministry of Education schools database. A questionnaire, mailed to school principals, assessed schools regarding 12 criteria for accreditation: policy, information, hats, 'play in the shade', sunscreen, clothing, role modelling, curriculum, planning, rescheduling, shade provision and review. Post-stratification weights (for achieving each criterion) were used to compensate for oversampling within some regions and differential response rates between regions, using the number of schools per region. 388 schools (representative in socioeconomic decile, size and type) participated. Less than 4% fully met accreditation criteria. Clothing (42%), curriculum delivery and shade (each 54%) requirements were met by the fewest schools. Staff role modelling (92%) was the most commonly met. Schools with uniforms tended to have more protective clothing expectations. Ongoing promotion is needed to consolidate gains and encourage comprehensive sun protection through policies, practices, environment and curriculum. Staff role modelling requirements may be strengthened by implementing existing occupational guidelines for mitigating UVR hazards. There is a need to further assist schools, particularly regarding sun protective clothing, curriculum delivery and environmental shade.

RNase MRP cleaves pre-tRNASer-Met in the tRNA maturation pathway.

PubMed

Saito, Yuichiro; Takeda, Jun; Adachi, Kousuke; Nobe, Yuko; Kobayashi, Junya; Hirota, Kouji; Oliveira, Douglas V; Taoka, Masato; Isobe, Toshiaki

2014-01-01

Ribonuclease mitochondrial RNA processing (RNase MRP) is a multifunctional ribonucleoprotein (RNP) complex that is involved in the maturation of various types of RNA including ribosomal RNA. RNase MRP consists of a potential catalytic RNA and several protein components, all of which are required for cell viability. We show here that the temperature-sensitive mutant of rmp1, the gene for a unique protein component of RNase MRP, accumulates the dimeric tRNA precursor, pre-tRNA(Ser-Met). To examine whether RNase MRP mediates tRNA maturation, we purified the RNase MRP holoenzyme from the fission yeast Schizosaccharomyces pombe and found that the enzyme directly and selectively cleaves pre-tRNA(Ser-Met), suggesting that RNase MRP participates in the maturation of specific tRNA in vivo. In addition, mass spectrometry-based ribonucleoproteomic analysis demonstrated that this RNase MRP consists of one RNA molecule and 11 protein components, including a previously unknown component Rpl701. Notably, limited nucleolysis of RNase MRP generated an active catalytic core consisting of partial mrp1 RNA fragments, which constitute "Domain 1" in the secondary structure of RNase MRP, and 8 proteins. Thus, the present study provides new insight into the structure and function of RNase MRP.

Comparison of the abilities of the plasma triglyceride/high-density lipoprotein cholesterol ratio and the metabolic syndrome to identify insulin resistance.

PubMed

Salazar, Martin R; Carbajal, Horacio A; Espeche, Walter G; Leiva Sisnieguez, Carlos E; March, Carlos E; Balbín, Eduardo; Dulbecco, Carlos A; Aizpurúa, Marcelo; Marillet, Alberto G; Reaven, Gerald M

2013-07-01

This study compares the ability of an elevated triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio, using sex-specific cut-points, to identify insulin-resistant individuals within a population without known cardiac disease or diabetes with that obtained using the diagnostic criteria of the metabolic syndrome (MetS). Measurements were made of waist circumference (WC), systolic and diastolic blood pressure, fasting plasma glucose, fasting plasma insulin (FPI), plasma TG and plasma HDL-C concentrations in 1102 women and 464 men. These data were used to classify subjects as being insulin resistant (FPI concentration in the upper quartile) and having the MetS or an elevated TG/HDL-C ratio (>2.5 and >3.5 for women and men, respectively). The sensitivity and specificity with which the two indices identified insulin-resistant subjects were similar (43% and 81% for TG/HDL-C ratio and 45% and 82% for MetS), as the number of individuals was found with either an elevated TG/HDL-C ratio (n = 386) or the MetS (n = 384). Eighty-one per cent of the individuals were identified concordantly. Cardio-metabolic risk profiles in 'low-risk' individuals identified by a low TG/HDL-C ratio were comparable to those who did not have the MetS, and this was also the case when comparing 'high-risk' groups identified by having the MetS or an elevated TG/HDL-C ratio. These findings suggest that TG/HDL-C concentration ratio is as adequate as MetS diagnosis to identify insulin-resistant subjects.

Walking and Metabolic Syndrome in Older Adults

PubMed Central

Strath, Scott; Swartz, Ann; Parker, Sarah; Miller, Nora; Cieslik, Linda

2010-01-01

Background Little data exists describing the impact that walking has on metabolic syndrome (MetS) in a multicultural sample of older adults. Methods Walking was measured via pedometer in 150 older adults from 4 different ethnic categories. Steps per day were classified as low (<3100 steps/d) or high (≥3100 steps/d) for statistical analyses. Results Occurrence of MetS was lower in the white (33%) versus non-white population (50%). Low steps/d were related to an increase in MetS for both white (OR = 96.8, 95% CI 12.3–764.6) and non-white individuals (OR = 4.5, 95% CI 1.8–11.3). Low steps/d also increased the odds for selected components of MetS in both the white and non-white groups. Conclusion Low levels of walking increase the likelihood of having MetS in both white and non-white older adults. Efforts to increase walking in older adults may decrease the likelihood of developing this clustering of disease risk factors. PMID:18209231

Diethylglyoxal bis(guanylhydrazone), a potent inhibitor of mammalian S-adenosylmethionine decarboxylase. Effects on cell proliferation and polyamine metabolism in L1210 leukemia cells.

PubMed

Svensson, F; Kockum, I; Persson, L

1993-07-21

The polyamines are cell constituents essential for growth and differentiation. S-Adenosylmethionine decarboxylase (AdoMetDC) catalyzes a key step in the polyamine biosynthetic pathway. Methylglyoxal bis(guanylhydrazone) (MGBG) is an anti-leukemic agent with a strong inhibitory effect against AdoMetDC. However, the lack of specificity limits the usefulness of MGBG. In the present report we have used an analog of MGBG, diethylglyoxal bis(guanylhydrazone) (DEGBG), with a much greater specificity and potency against AdoMetDC, to investigate the effects of AdoMetDC inhibition on cell proliferation and polyamine metabolism in mouse L1210 leukemia cells. DEGBG was shown to effectively inhibit AdoMetDC activity in exponentially growing L1210 cells. The inhibition of AdoMetDC was reflected in a marked decrease in the cellular concentrations of spermidine and spermine. The concentration of putrescine, on the other hand, was greatly increased. Treatment with DEGBG resulted in a compensatory increase in the synthesis of AdoMetDC demonstrating an efficient feedback control. Cells seeded in the presence of DEGBG ceased to grow after a lag period of 1-2 days, indicating that the cells contained an excess of polyamines which were sufficient for one or two cell cycles in the absence of polyamine synthesis. The present results indicate that analogs of MGBG, having a greater specificity against AdoMetDC, might be valuable for studies concerning polyamines and cell proliferation.

The unique functional role of the C-HS hydrogen bond in the substrate specificity and enzyme catalysis of type 1 methionine aminopeptidase.

PubMed

Reddi, Ravikumar; Singarapu, Kiran Kumar; Pal, Debnath; Addlagatta, Anthony

2016-07-19

It is intriguing how nature attains recognition specificity between molecular interfaces where there is no apparent scope for classical hydrogen bonding or polar interactions. Methionine aminopeptidase (MetAP) is one such enzyme where this fascinating conundrum is at play. In this study, we demonstrate that a unique C-HS hydrogen bond exists between the enzyme methionine aminopeptidase (MetAP) and its N-terminal-methionine polypeptide substrate, which allows specific interaction between apparent apolar interfaces, imposing a strict substrate recognition specificity and efficient catalysis, a feature replicated in Type I MetAPs across all kingdoms of life. We evidence this evolutionarily conserved C-HS hydrogen bond through enzyme assays on wild-type and mutant MetAP proteins from Mycobacterium tuberculosis that show a drastic difference in catalytic efficiency. The X-ray crystallographic structure of the methionine bound protein revealed a conserved water bridge and short contacts involving the Met side-chain, a feature also observed in MetAPs from other organisms. Thermal shift assays showed a remarkable 3.3 °C increase in melting temperature for methionine bound protein compared to its norleucine homolog, where C-HS interaction is absent. The presence of C-HS hydrogen bonding was also corroborated by nuclear magnetic resonance spectroscopy through a change in chemical shift. Computational chemistry studies revealed the unique role of the electrostatic environment in facilitating the C-HS interaction. The significance of this atypical hydrogen bond is underscored by the fact that the function of MetAP is essential for any living cell.

Metabotropic glutamate receptor agonists potentiate a slow afterdepolarization in CNS neurons

NASA Technical Reports Server (NTRS)

Zheng, F.; Gallagher, J. P.

1992-01-01

We have previously reported that, in the rat dorsolateral septal nucleus (DLSN), metabotropic glutamate receptor (met-GluR) agonists evoked a slow depolarization accompanied by an increase in membrane conductance and burst firing. We have speculated that the burst firing elicited by met-GluR agonists may be due to activation or enhancement of a non-specific cation current, which exists in some DLSN neurons. Now we report that a slow afterdepolarization (sADP) mediated by a non-specific cation current was potentiated by both 1S,3R-ACPD and quisqualate. In addition, met-GluR agonists unmask a sADP in DLSN neurons which did not show a sADP under control conditions. Our data suggest that a non-specific cation current can be potentiated by activation of the met-GluR.

Broadband infrared beam splitter for spaceborne interferometric infrared sounder.

PubMed

Yu, Tianyan; Liu, Dingquan; Qin, Yang

2014-10-01

A broadband infrared beam splitter (BS) on ZnSe substrate used for the spaceborne interferometric infrared sounder (SIIRS) is studied in the spectral range of 4.44-15 μm. Both broadband antireflection coating and broadband beam-splitter coating in this BS are designed and tested. To optimize the optical properties and the stability of the BS, suitable infrared materials were selected, and improved deposition techniques were applied. The designed structures matched experimental data well, and the properties of the BS met the application specification of SIIRS.

Bioorthogonal Modification of the Major Sheath Protein of Bacteriophage M13: Extending the Versatility of Bionanomaterial Scaffolds.

PubMed

Urquhart, Taylor; Daub, Elisabeth; Honek, John Frank

2016-10-19

With a mass of ∼1.6 × 10 7 Daltons and composed of approximately 2700 proteins, bacteriophage M13 has been employed as a molecular scaffold in bionanomaterials fabrication. In order to extend the versatility of M13 in this area, residue-specific unnatural amino acid incorporation was employed to successfully display azide functionalities on specific solvent-exposed positions of the pVIII major sheath protein of this bacteriophage. Employing a combination of engineered mutants of the gene coding for the pVIII protein, the methionine (Met) analog, l-azidohomoalanine (Aha), and a suitable Escherichia coli Met auxotroph for phage production, conditions were developed to produce M13 bacteriophage labeled with over 350 active azides (estimated by fluorescent dye labeling utilizing a strain-promoted azide-alkyne cycloaddition) and capable of azide-selective attachment to 5 nm gold nanoparticles as visualized by transmission electron microscopy. The capability of this system to undergo dual labeling utilizing both chemical acylation and bioorthogonal cycloaddition reactions was also verified. The above stratagem should prove particularly advantageous in the preparation of assemblies of larger and more complex molecular architectures based on the M13 building block.

Does a brief suicide prevention gatekeeper training program enhance observed skills?

PubMed Central

Cross, Wendi; Matthieu, Monica M.; Lezine, DeQuincy; Knox, Kerry L.

2010-01-01

Background Suicide is a significant public health problem worldwide that requires evidence-based prevention efforts. One approach to prevention is gatekeeper training. Gatekeeper training programs for community members have demonstrated positive changes in knowledge and attitudes about suicide. Changes in gatekeeper skills have not been well established. Aims To assess and predict the impact of a brief, gatekeeper training on community members’ observed skills. Methods Participants in a community gatekeeper training were employees at US universities. 50 participants were randomly selected for skills assessment and videotaped interacting with a standardized actor prior to and following training. Tapes were reliability rated for general and suicide-specific skills. Results Gatekeeper skills increased from pre- to posttest: 10% of participants met criteria for acceptable gatekeeper skills before training, while 54% met criteria after training. Pretraining variables did not predict increased skills. Limitations Results do not provide conclusions about the relationship between observed gatekeeper skills and actual use of those skills in the future. Conclusions Gatekeeper training enhances suicide-specific skills for the majority of participants. Other strategies, such as behavioral rehearsal, may be necessary to enhance skills in the remaining participants. PMID:20573609

Development of a Novel SPECT Tracer to Image c-Met Expression in Non-Small Cell Lung Cancer in a Human Tumor Xenograft.

PubMed

Han, Zhaoguo; Xiao, Yadi; Wang, Kai; Yan, Ji; Xiao, Zunyu; Fang, Fang; Jin, Zhongnan; Liu, Yang; Sun, Xilin; Shen, Baozhong

2018-05-18

Rationale: Elevated expression of the c-Met receptor plays a crucial role in cancers. In non-small cell lung cancer (NSCLC), aberrant activation of c-Met signaling pathway contributes to tumorigenesis and cancer progression, and may mediate acquired resistance to epidermal growth factor receptor-targeted therapy. c-Met is therefore emerging as a promising therapeutic target for treating NSCLC, and the methods for noninvasive in vivo assessment of c-Met expression will improve NSCLC treatment and diagnosis. Methods: A new peptide-based (cMBP) radiotracer targeting c-Met, 99m Tc-hydrazine nicotinamide (HYNIC)-cMBP, was developed for single photon emission computed tomography (SPECT) imaging. Cell uptake assays were performed on two NSCLC cell lines with different c-Met expression: H1993 (high expression) and H1299 (no expression). In vivo tumor specificity was assessed by SPECT imaging in tumor-bearing mice at 0.5, 1, 2 and 4 h after injection of the probe. Blocking assays, biodistribution and autoradiography were also conducted to determine probe specificity. Results: 99m Tc-HYNIC-cMBP was prepared with high efficiency and showed higher uptake in H1993 cells than H1299 cells. Biodistribution and autoradiography also showed significantly higher accumulation of 99m Tc-HYNIC-cMBP in H1993 tumors than H1299 (H1993: 4.74±1.43 %ID/g and H1299: 1.00±0.37 %ID/g at 0.5h, p<0.05). H1993 tumors were clearly visualized at 0.5h in SPECT images, whereas H1299 tumors were not observed at any time. Specificity of 99m Tc-HYNIC-cMBP to c-Met was demonstrated by competitive block with excess un-radiolabeled peptide. Conclusion: We developed a novel SPECT tracer, 99m Tc-HYNIC-cMBP, for c-Met-targeted imaging in NSCLC that specifically bound to c-Met with favorable pharmacokinetics in vitro and in vivo. Copyright © 2018 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Phase I Trial of Anti-MET Monoclonal Antibody in MET-Overexpressed Refractory Cancer.

PubMed

Lee, Jeeyun; Kim, Seung Tae; Park, Sungju; Lee, Sujin; Park, Se Hoon; Park, Joon Oh; Lim, Ho Yeong; Ahn, Hongmo; Bok, Haesook; Kim, Kyoung-Mee; Ahn, Myung Ju; Kang, Won Ki; Park, Young Suk

2018-06-01

Samsung Advance Institute of Technology-301 (SAIT301) is a human immunoglobulin G2 antibody that can specifically target mesenchymal epithelial transition factor (c-MET). This novel antibody has higher priority over hepatocyte growth factors when binding to the Sema domain of c-MET and accelerates the internalization and degradation of c-MET, proving its powerful antitumor activities in intra- as well as extracellular areas. SAIT301 was administered intravenously once every 3 weeks in c-MET overexpressed solid tumor patients, focusing on metastatic colorectal cancer (CRC) according to common clinical phase I criteria. Dose escalation was performed according to a modified Fibonacci design, following the conventional 3+3 design. The purpose of this phase I study was to assess the safety profile, to establish the recommended dose for clinical phase II studies and to assess potential anticancer activity of the compound. Sixteen patients with a median age of 56 (range, 39-69) years were enrolled in the study. The most common adverse events were decreased appetite (50.0%), hypophosphatemia, fatigue and dizziness (25.0%, respectively), and diarrhea, blood alkaline phosphatase increased and dyspnea (18.8%, respectively). For tumor response, no patients achieved complete response. One (9.1%) CRC patient had a partial response in the 1.23 mg/kg group, 4 (36.4%) patients achieved stable disease (2 in the 0.41 mg/kg group, 2 in the 1.23 mg/kg group, 0 in the 3.69 mg/kg group, and 1 in the 8.61 mg/kg group). Because of the increase in dose-limiting toxicities (DLTs) at 8.61 mg/kg, the 3.69 mg/kg dose was considered the maximum tolerated dose and selected for further assessment in phase II. We successfully completed a phase I trial with MET antibody in a MET-overexpressed patient population focusing on CRC, and found that the DLTs were alkaline phosphatase elevation or hypophosphatemia. The recommended dose of SAIT301 for phase II is the dose of 3.69 mg/kg. Copyright © 2018 Elsevier Inc. All rights reserved.

Decreased muscle mass is not an independent risk factor for metabolic syndrome in Korean population aged 70 or older.

PubMed

Koo, Hyung Suk; Kim, Moon Jong; Kim, Kwang-Min; Kim, Young-Sang

2015-04-01

The association of low muscle mass with cardiometabolic risks is still controversial. The aim of this study was to investigate the relationship between low muscle mass and metabolic syndrome (MetS) according to the various muscle mass indices and to evaluate the influence of muscle mass on MetS independent of fat mass. Cross-sectional study About 841 men and 1106 women aged 70 or older from Korea National Health and Nutrition Examination Survey 2008-2010 MEASUREMENTS: We used various muscle mass indices: appendicular skeletal muscle mass (ASM) divided by height squared (ASM/Ht(2) ), ASM divided by body weight (ASM/Wt) and ASM adjusted for height and fat mass (residual). Low muscle mass is defined as ASM/Ht(2) and ASM/Wt below 2 SD of the sex-specific mean for healthy young adults. The sex-specific lowest quintile of the distribution of the residual was regarded as low muscle mass. The prevalence of MetS was higher in the population with low muscle mass defined by ASM/Wt, but lower in those defined by ASM/Ht(2) . However, after stratification according to the central obesity, low muscle mass was barely related with MetS. Meanwhile, when both ASM and fat mass were included in a logistic regression model, the odds ratios of 1 SD change of ASM for MetS were 1·07 (0·85-1·34) for men and 1·24 (1·04-1·47) for women, respectively. The relationship between low muscle mass and MetS was different according to the various muscle mass indices. After controlling the influence of fat mass, decreased muscle mass was not an independent risk factor for MetS. © 2014 John Wiley & Sons Ltd.

Leisure-time physical activity and metabolic syndrome plus depressive symptoms in the FIN-D2D survey.

PubMed

Korniloff, Katariina; Katariina, Korniloff; Häkkinen, Arja; Arja, Häkkinen; Kautiainen, Hannu; Hannu, Kautiainen; Koponen, Hannu; Hannu, Koponen; Peltonen, Markku; Markku, Peltonen; Mäntyselkä, Pekka; Pekka, Mäntyselkä; Oksa, Heikki; Heikki, Oksa; Kampman, Olli; Olli, Kampman; Vanhala, Mauno; Mauno, Vanhala

2010-12-01

To examine the association between leisure-time physical activity (LTPA) and simultaneous presence of metabolic syndrome (MetS) and depressive symptoms (DS) based on a population-based FIN-D2D cross-sectional survey conducted in 2007. 4500 randomly selected Finnish men and women aged 45-74 years were initially enrolled; 2868 (64%) attended a health examination. Participants with complete information (n=2778) were grouped into three LTPA categories: low, moderate and high. MetS was based on the National Cholesterol Education Program criteria and DS on the Beck Depression Inventory (≥10 points). The prevalence of MetS and DS were 53% and 15%, respectively; the prevalence of simultaneous MetS and DS was 10%. The proportion of subjects with MetS, DS and simultaneous presence of MetS and DS increased with decreasing LTPA (p<0.001). On multivariate ordered analysis, LTPA was related to education years, household income, smoking, and the presence of MetS only, DS only and simultaneous MetS and DS. The prevalence of simultaneous MetS and DS was higher in participants with low LTPA compared with participants with high LTPA. Furthermore, LTPA level was associated with socioeconomic status and other health related outcomes, outlining the importance of LTPA as part of the general health promotion. Copyright © 2010 Elsevier Inc. All rights reserved.

Hepatocyte specific deletion of c-Met leads to the development of severe non-alcoholic steatohepatitis in mice.

PubMed

Kroy, Daniela C; Schumacher, Fabienne; Ramadori, Pierluigi; Hatting, Maximilian; Bergheim, Ina; Gassler, Nikolaus; Boekschoten, Mark V; Müller, Michael; Streetz, Konrad L; Trautwein, Christian

2014-10-01

Non-alcoholic-fatty-liver disease (NAFLD) is part of the metabolic syndrome. The spectrum of NAFLD includes NASH (non-alcoholic steatohepatitis), which is characterised by progressive inflammation associated with oxidative stress and apoptosis, finally triggering liver cirrhosis and hepatocellular carcinoma. HGF (hepatocyte growth factor)/mesenchymal-epithelial transition factor (c-Met) receptor signalling is known to activate distinct intracellular pathways mediating among others anti-apoptotic properties to hepatocytes. Therefore, the aim was to characterise the role of c-Met during NASH development. Hepatocyte specific c-Met knockout mice (c-MetΔ(hepa)) using the cre-loxP system and wild type controls (c-Met(loxP/loxP)) were fed a methionine-choline deficient (MCD) diet. MCD feeding triggered massive steatosis, decreased survival and higher transaminases in c-MetΔ(hepa) livers compared to c-Met(loxP/loxP). Gene array analysis demonstrated that genes involved in fatty acid metabolism were strongly upregulated in c-MetΔ(hepa) livers correlating with higher amounts of hepatic free fatty acids. Consequently, c-MetΔ(hepa) mice showed significantly more TUNEL positive cells and more superoxide anion production than c-Met(loxPloxP) animals. Additionally, c-MetΔ(hepa) livers showed significantly larger fractions of infiltrating neutrophils, macrophages, and cytotoxic T cells. These changes correlated with an enhanced progression of liver fibrosis as evidenced by higher collagen deposition in c-MetΔ(hepa) livers. As increased apoptosis was a prominent feature in c-MetΔ(hepa) livers, we generated c-Met/Casp8Δ(hepa) double knockout mice. In these animals compared to c-MetΔ(hepa) animals the increase in apoptosis could be reverted. c-Met deletion in hepatocytes triggers NASH progression. A prominent mechanism is higher fatty acid accumulation and increased apoptosis, which in part can be reverted by blocking caspase 8. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Clinical utility of metabolic syndrome severity scores: considerations for practitioners

PubMed Central

DeBoer, Mark D; Gurka, Matthew J

2017-01-01

The metabolic syndrome (MetS) is marked by abnormalities in central obesity, high blood pressure, high triglycerides, low high-density lipoprotein-cholesterol, and high fasting glucose and appears to be produced by underlying processes of inflammation, oxidative stress, and adipocyte dysfunction. MetS has traditionally been classified based on dichotomous criteria that deny that MetS-related risk likely exists as a spectrum. Continuous MetS scores provide a way to track MetS-related risk over time. We generated MetS severity scores that are sex- and race/ethnicity-specific, acknowledging that the way MetS is manifested may be different by sex and racial/ethnic subgroup. These scores are correlated with long-term risk for type 2 diabetes mellitus and cardiovascular disease. Clinical use of scores like these provide a potential opportunity to identify patients at highest risk, motivate patients toward lifestyle change, and follow treatment progress over time. PMID:28255250

The autism susceptibility gene met regulates zebrafish cerebellar development and facial motor neuron migration

PubMed Central

Elsen, Gina E.; Choi, Louis Y.; Prince, Victoria E.; Ho, Robert K.

2009-01-01

During development, Met signaling regulates a range of cellular processes including growth, differentiation, survival and migration. The Met gene encodes a tyrosine kinase receptor, which is activated by Hgf (hepatocyte growth factor) ligand. Altered regulation of human MET expression has been implicated in autism. In mouse, Met signaling has been shown to regulate cerebellum development. Since abnormalities in cerebellar structure have been reported in some autistic patients, we have used the zebrafish to address the role of Met signaling during cerebellar development and thus further our understanding of the molecular basis of autism. We find that zebrafish met is expressed in the cerebellar primordium, later localizing to the ventricular zone (VZ), with the hgf1 and hgf2 ligand genes expressed in surrounding tissues. Morpholino knockdown of either Met or its Hgf ligands leads to a significant reduction in the size of the cerebellum, primarily as a consequence of reduced proliferation. Met signaling knockdown disrupts specification of VZ-derived cell types, and also reduces granule cell numbers, due to an early effect on cerebellar proliferation and/or as an indirect consequence of loss of signals from VZ-derived cells later in development. These patterning defects preclude analysis of cerebellar neuronal migration, but we have found that Met signaling is necessary for migration of hindbrain facial motor neurons. In summary, we have described roles for Met signaling in coordinating growth and cell type specification within the developing cerebellum, and in migration of hindbrain neurons. These functions may underlie the correlation between altered MET regulation and Autism Spectrum Disorders. PMID:19732764

Cbl-independent degradation of Met: ways to avoid agonism of bivalent Met-targeting antibody.

PubMed

Lee, J M; Kim, B; Lee, S B; Jeong, Y; Oh, Y M; Song, Y-J; Jung, S; Choi, J; Lee, S; Cheong, K H; Kim, D U; Park, H W; Han, Y K; Kim, G W; Choi, H; Song, P H; Kim, K A

2014-01-02

The Met receptor tyrosine kinase, found to be constitutively activated in many tumors, has become a leading target for cancer therapy. Disruptions in Met downregulation have been associated with aggressive tumor progression with several therapeutic strategies addressing this aspect of Met biology. Castias B-lineage lymphoma (Cbl) E3 ligase-mediated degradation, which attenuates Met signaling via ligand-dependent Met internalization, is a major negative regulator of Met expression. It is believed that one of the mechanisms by which the therapeutic anti-Met antibodies induce cancer cell death in Met overexpressing tumors is via internalization and subsequent degradation of Met from the cell surface. However, a previously reported Met-targeting antibody demonstrated intrinsic agonistic activity while being capable of inducing Cbl-mediated degradation of Met, suggesting that Cbl-mediated degradation requires receptor activation and impedes therapeutic application. We have developed a potent and selective bivalent Met-targeting antibody (SAIT301) that invokes Met degradation using an alternative regulator LRIG1. In this report, we demonstrate that LRIG1 mediates degradation of Met by SAIT301 and this degradation does not require Met activation. Furthermore, SAIT301 was able to downregulate Met and dramatically inhibit growth of tumors with low or no Cbl expression, as well as tumors with Met exon 14 deletion that prevents Met binding to Cbl. In summary, we demonstrate the enhanced therapeutic potential of a novel tumor-inhibiting anti-Met antibody, SAIT301, which utilizes a Cbl-independent, LRIG1-mediated Met degradation pathway and thereby avoids the agonism that limits the effectiveness of previously reported anti-Met antibodies.

Evaluation of Cobas Integra 800 under simulated routine conditions in six laboratories.

PubMed

Redondo, Francisco L; Bermudez, Pilar; Cocco, Claudio; Colella, Francesca; Graziani, Maria Stella; Fiehn, Walter; Hierla, Thomas; Lemoël, Gisèle; Belliard, AnneMarie; Manene, Dieudonne; Meziani, Mourad; Liebel, Maryann; McQueen, Matthew J; Stockmann, Wolfgang

2003-03-01

The new selective access analyser Cobas Integra 800 from Roche Diagnostics was evaluated in an international multicentre study at six sites. Routine simulation experiments showed good performance and full functionality of the instrument and provocation of anomalous situations generated no problems. The new features on Cobas Integra 800, namely clot detection and dispensing control, worked according to specifications. The imprecision of Cobas Integra 800 fulfilled the proposed quality specifications regarding imprecision of analytical systems for clinical chemistry with few exceptions. Claims for linearity, drift, and carry-over were all within the defined specifications, except urea linearity. Interference exists in some cases, as could be expected due to the chemistries applied. Accuracy met the proposed quality specifications, except in some special cases. Method comparisons with Cobas Integra 700 showed good agreement; comparisons with other analysis systems yielded in several cases explicable deviations. Practicability of Cobas Integra 800 met or exceeded the requirements for more than 95% of all attributes rated. The strong points of the new analysis system were reagent handling, long stability of calibration curves, high number of tests on board, compatibility of the sample carrier to other Roche systems, and the sample integrity check for more reliable analytical results. The improvement of the workflow offered by the 5-position rack and STAT handling like on Cobas Integra 800 makes the instrument attractive for further consolidation in the medium-sized laboratory, for dedicated use of special analytes, and/or as back-up in the large routine laboratory.

Regional metabolism of Met-enkephalin and cholecystokinin on intact ratbrain slices: characterization of specific peptidases.

PubMed

Konkoy, C S; Davis, T P

1995-12-01

The metabolism of Met-enkephalin and cholecystokinin (CCK) 8-(sulfated) by intact microslices was studied in rat brain regions. Incubation of brain slices with Met-enkephalin (400 microM) resulted in a linear rate of disappearance of parent peptide and appearance of metabolic fragments whose rate of accumulation was specific to brain region. The degradative rate (pmol/min/mg of protein) of Met-enkephalin was high in caudate-putamen (5,160 +/- 120) and lower in nucleus accumbens (3,630 +/- 110) and frontal cortex (3,180 +/- 120). Inhibition of aminopeptidases decreased Met-enkephalin degradation (50-97% vs. control) in frontal cortex but was less effective in caudate-putamen (20-34%). Tyr-Gly-Gly and Phe-Met were recovered in caudate-putamen and nucleus accumbens, whereas negligible quantities of these fragments were recovered from frontal cortex. Phosphoramidon, an inhibitor of neutral endopeptidase 24.11, decreased Met-enkephalin degradation in caudate-putamen (14%) but had no effect on that in frontal cortex. A cocktail of bestatin or leuhistin (inhibitors of aminopeptidases), phosphoramidon, and captopril (an inhibitor of angiotensin converting enzyme) protected Met-enkephalin from degradation (recovery > 95%) in caudate-putamen. CCK 8-(sulfated) degradation on slices from caudate-putamen, nucleus accumbens, and frontal cortex was not altered by inhibitors of neutral endopeptidase 24.11, metalloendopeptidase 24.15, angiotensin converting enzyme, or thiol proteases. Inhibitors of either aminopeptidases or serine proteases produced small reductions (13-30%) in CCK degradation in each region. These data provide evidence for regional and structural specificity in terminating the actions of neuropeptides.

Optimized probability sampling of study sites to improve generalizability in a multisite intervention trial.

PubMed

Kraschnewski, Jennifer L; Keyserling, Thomas C; Bangdiwala, Shrikant I; Gizlice, Ziya; Garcia, Beverly A; Johnston, Larry F; Gustafson, Alison; Petrovic, Lindsay; Glasgow, Russell E; Samuel-Hodge, Carmen D

2010-01-01

Studies of type 2 translation, the adaption of evidence-based interventions to real-world settings, should include representative study sites and staff to improve external validity. Sites for such studies are, however, often selected by convenience sampling, which limits generalizability. We used an optimized probability sampling protocol to select an unbiased, representative sample of study sites to prepare for a randomized trial of a weight loss intervention. We invited North Carolina health departments within 200 miles of the research center to participate (N = 81). Of the 43 health departments that were eligible, 30 were interested in participating. To select a representative and feasible sample of 6 health departments that met inclusion criteria, we generated all combinations of 6 from the 30 health departments that were eligible and interested. From the subset of combinations that met inclusion criteria, we selected 1 at random. Of 593,775 possible combinations of 6 counties, 15,177 (3%) met inclusion criteria. Sites in the selected subset were similar to all eligible sites in terms of health department characteristics and county demographics. Optimized probability sampling improved generalizability by ensuring an unbiased and representative sample of study sites.

Phloem-Specific Methionine Recycling Fuels Polyamine Biosynthesis in a Sulfur-Dependent Manner and Promotes Flower and Seed Development1[OPEN

PubMed Central

Hajirezaei, Mohammad R.

2016-01-01

The Yang or Met Cycle is a series of reactions catalyzing the recycling of the sulfur (S) compound 5′-methylthioadenosine (MTA) to Met. MTA is produced as a by-product in ethylene, nicotianamine, and polyamine biosynthesis. Whether the Met Cycle preferentially fuels one of these pathways in a S-dependent manner remained unclear so far. We analyzed Arabidopsis (Arabidopsis thaliana) mutants with defects in the Met Cycle enzymes 5-METHYLTHIORIBOSE-1-PHOSPHATE-ISOMERASE1 (MTI1) and DEHYDRATASE-ENOLASE-PHOSPHATASE-COMPLEX1 (DEP1) under different S conditions and assayed the contribution of the Met Cycle to the regeneration of S for these pathways. Neither mti1 nor dep1 mutants could recycle MTA but showed S-dependent reproductive failure, which was accompanied by reduced levels of the polyamines putrescine, spermidine, and spermine in mutant inflorescences. Complementation experiments with external application of these three polyamines showed that only the triamine spermine could specifically rescue the S-dependent reproductive defects of the mutant plants. Furthermore, expressing gene-reporter fusions in Arabidopsis showed that MTI1 and DEP1 were mainly expressed in the vasculature of all plant parts. Phloem-specific reconstitution of Met Cycle activity in mti1 and dep1 mutant plants was sufficient to rescue their S-dependent mutant phenotypes. We conclude from these analyses that phloem-specific S recycling during periods of S starvation is essential for the biosynthesis of polyamines required for flowering and seed development. PMID:26662272

Eicosanoids in Metabolic Syndrome

PubMed Central

Hardwick, James P.; Eckman, Katie; Lee, Yoon Kwang; Abdelmegeed, Mohamed A.; Esterle, Andrew; Chilian, William M.; Chiang, John Y.; Song, Byoung-Joon

2013-01-01

Chronic persistent inflammation plays a significant role in disease pathology of cancer, cardiovascular disease, and metabolic syndrome (MetS). MetS is a constellation of diseases that include obesity, diabetes, hypertension, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia. Nonalcoholic fatty liver disease (NAFLD) is associated with many of the MetS diseases. These metabolic derangements trigger a persistent inflammatory cascade, which includes production of lipid autacoids (eicosanoids) that recruit immune cells to the site of injury and subsequent expression of cytokines and chemokines that amplify the inflammatory response. In acute inflammation, the transcellular synthesis of antiinflammatory eicosanoids resolve inflammation, while persistent activation of the autacoid-cytokine-chemokine cascade in metabolic disease leads to chronic inflammation and accompanying tissue pathology. Many drugs targeting the eicosanoid pathways have been shown to be effective in the treatment of MetS, suggesting a common linkage between inflammation, MetS and drug metabolism.The cross-talk between inflammation and MetS seems apparent because of the growing evidence linking immune cell activation and metabolic disorders such as insulin resistance, dyslipidemia, and hypertriglyceridemia. Thus modulation of lipid metabolism through either dietary adjustment or selective drugs may become a new paradigm in the treatment of metabolic disorders. This review focuses on the mechanisms linking eicosanoid metabolism to persistent inflammation and altered lipid and carbohydrate metabolism in MetS. PMID:23433458

Intra-thoracic fat volume is associated with myocardial infarction in patients with metabolic syndrome.

PubMed

Jolly, Umjeet S; Soliman, Abraam; McKenzie, Charles; Peters, Terry; Stirrat, John; Nevis, Immaculate; Brymer, Matthew; Joy, Tisha; Drangova, Maria; White, James A

2013-09-10

Visceral adiposity is increased in those with Metabolic Syndrome (MetS) and atherosclerotic disease burden. In this study we evaluate for associations between intra-thoracic fat volume (ITFV) and myocardial infarction (MI) in patients with MetS. Ninety-four patients with MetS, MI or both were identified from a cardiovascular CMR clinical registry. MetS was defined in accordance to published guidelines; where-as MI was defined as the presence of subendocardial-based injury on late gadolinium enhancement imaging in a coronary vascular distribution. A healthy control group was also obtained from the same registry. Patients were selected into the following groups: MetS+/MI- (N = 32), MetS-/MI + (N = 30), MetS+/MI + (N = 32), MetS-/MI- (N = 16). ITFV quantification was performed using signal threshold analysis of sequential sagittal CMR datasets (HASTE) and indexed to body mass index. The mean age of the population was 59.8 ± 12.5 years. MetS+ patients (N=64) demonstrated a significantly higher indexed ITFV compared to MetS- patients (p = 0.05). Patients in respective MetS-/MI-, MetS+/MI-, MetS-/MI+, and MetS+/MI + study groups demonstrated a progressive elevation in the indexed ITFV (22.3 ± 10.6, 28.6 ± 12.6, 30.6 ± 12.3, and 35.2 ± 1.4 ml/kg/m(2), (p = 0.002)). Among MetS+ patients those with MI showed a significantly higher indexed ITFV compared to those without MI (p = 0.02). ITFV is elevated in patients with MetS and incrementally elevated among those with evidence of prior ischemic myocardial injury. Accordingly, the quantification of ITFV may be a valuable marker of myocardial infarction risk among patients with MetS and warrants further investigation.

Thiamine and its phosphate esters in relation to cardiometabolic risk factors in Saudi Arabs.

PubMed

Al-Daghri, Nasser M; Al-Attas, Omar S; Alkharfy, Khalid M; Alokail, Majed S; Abd-Alrahman, Sherif H; Sabico, Shaun

2013-09-23

Thiamine deficiency has suggested to be linked to several insulin-resistance complications. In this study, we aim to associate circulating thiamine levels among cardiometabolic parameters in an Arab cohort using a simple, sensitive, rapid and selective high-performance liquid chromatography (HPLC) method that has recently been developed. A total of 236 randomly selected, consenting Saudi adult participants (166 males and 70 females) were recruited and screened for the presence of the metabolic syndrome (MetS) using the modified National Cholesterol Education Program-Adult Treatment Panel III definition. Blood thiamine and its derivatives were quantified using HPLC. A total of 140 participants (53.9%) had MetS. The levels of thiamine and its derivatives of those with MetS were not significantly different from those without. However, hypertensive subjects had significantly higher urinary thiamine (P = 0.03) as well as significantly lower levels of thiamine diphosphate (TDP) (P = 0.01) and total thiamine (P = 0.02) than the normotensive subjects, even after adjusting for age and body mass index (BMI). Furthermore, age- and BMI-matched participants with elevated blood glucose levels had significantly lower levels of thiamine monophosphate (P = 0.020), TDP (P < 0.001) and total thiamine (P < 0.001) and significantly elevated levels of urinary thiamine (P = 0.005) compared to normoglycemic participants. Low thiamine levels are associated with elevated blood glucose and hypertension in Saudi adults. Determination of thiamine status may be considered and corrected among patients with, or at high risk for, MetS, but the question whether thiamine deficiency correction translates to improved cardiometabolic status needs further longitudinal investigation.

A Critical Review of Search Strategies Used in Recent Systematic Reviews Published in Selected Prosthodontic and Implant-Related Journals: Are Systematic Reviews Actually Systematic?

PubMed

Layton, Danielle

The aim of this study was to outline how search strategies can be systematic, to examine how the searches in recent systematic reviews in prosthodontic and implant-related journals were structured, and to determine whether the search strategies used in those articles were systematic. A total of 103 articles published as systematic reviews and indexed in Medline between January 2013 and May 2016 were identified from eight prosthodontic and implant journals and reviewed. The search strategies were considered systematic when they met the following criteria: (1) more than one electronic database was searched, (2) more than one searcher was clearly involved, (3) both text words and indexing terms were clearly included in the search strategy, (4) a hand search of selected journals or reference lists was undertaken, (5) gray research was specifically sought, and (6) the articles were published in English and at least one other language. The data were tallied and qualitatively assessed. The majority of articles reported on implants (54%), followed by tooth-supported fixed prosthodontics (13%). A total of 23 different electronic resources were consulted, including Medline (by 100% of articles), the Cochrane Library (52%), and Embase (37%). The majority consulted more than one electronic resource (71%), clearly included more than one searcher (73%), and employed a hand search of either selected journals or reference lists (86%). Less than half used both text words and indexing terms to identify articles (42%), while 15% actively sought gray research. Articles published in languages other than English were considered in 63 reviews, but only 14 had no language restrictions. Of the 103 articles, 5 completed search strategies that met all 6 criteria, and a further 12 met 5 criteria. Two articles did not fulfill any of the criteria. More than 95% of recent prosthodontic and implant review articles published in the selected journals failed to use search strategies that were systematic, and this undermines the conclusions. Many resources are available to help investigators design search strategies for systematic reviews that minimize the risk of omitting important data, including the simple criteria presented in this paper.

HGF/MET-directed therapeutics in gastroesophageal cancer: a review of clinical and biomarker development.

PubMed

Hack, Stephen P; Bruey, Jean-Marie; Koeppen, Hartmut

2014-05-30

Aberrant activation of the HGF/MET signaling axis has been strongly implicated in the malignant transformation and progression of gastroesophageal cancer (GEC). MET receptor overexpression in tumor samples from GEC patients has been consistently correlated with an aggressive metastatic phenotype and poor prognosis. In preclinical GEC models, abrogation of HGF/MET signaling has been shown to induce tumor regression as well as inhibition of metastatic dissemination. Promising clinical results in patient subsets in which MET is overexpressed have spurned several randomized studies of HGF/MET-directed agents, including two pivotal global Phase III trials. Available data highlight the need for predictive biomarkers in order to select patients most likely to benefit from HGF/MET inhibition. In this review, we discuss the current knowledge of mechanisms of MET activation in GEC, the current status of the clinical evaluation of MET-targeted therapies in GEC, characteristics of ongoing randomized GEC trials and the associated efforts to identify and validate biomarkers. We also discuss the considerations and challenges for HGF/MET inhibitor drug development in the GEC setting.

HGF/MET-directed therapeutics in gastroesophageal cancer: a review of clinical and biomarker development

PubMed Central

Hack, Stephen P.; Bruey, Jean-Marie; Koeppen, Hartmut

2014-01-01

Aberrant activation of the HGF/MET signaling axis has been strongly implicated in the malignant transformation and progression of gastroesophageal cancer (GEC). MET receptor overexpression in tumor samples from GEC patients has been consistently correlated with an aggressive metastatic phenotype and poor prognosis. In preclinical GEC models, abrogation of HGF/MET signaling has been shown to induce tumor regression as well as inhibition of metastatic dissemination. Promising clinical results in patient subsets in which MET is overexpressed have spurned several randomized studies of HGF/MET-directed agents, including two pivotal global Phase III trials. Available data highlight the need for predictive biomarkers in order to select patients most likely to benefit from HGF/MET inhibition. In this review, we discuss the current knowledge of mechanisms of MET activation in GEC, the current status of the clinical evaluation of MET-targeted therapies in GEC, characteristics of ongoing randomized GEC trials and the associated efforts to identify and validate biomarkers. We also discuss the considerations and challenges for HGF/MET inhibitor drug development in the GEC setting. PMID:24930887

Heat-shock protein 27 (HSP27, HSPB1) is synthetic lethal to cells with oncogenic activation of MET, EGFR and BRAF.

PubMed

Konda, John D; Olivero, Martina; Musiani, Daniele; Lamba, Simona; Di Renzo, Maria F

2017-06-01

The small heat-shock protein of 27 kDa (HSP27) is highly expressed in many cancers and is associated with aggressive tumour behaviour, metastasis, poor prognosis and resistance to chemotherapy. We aimed at assessing the role of HSP27 in modulating responses to target therapies. We selected several oncogene-addicted cancer cell lines, which undergo either cell cycle blockade or cell death in response to agents that target the specific oncogene. Surprisingly, HSP27 suppression alone resulted in the apoptotic death of MET-addicted EBC-1 lung cancer cells, epidermal growth factor receptor (EGFR)-addicted colorectal carcinoma (CRC) DiFi cells and BRAF-addicted CRC COLO205 and OXCO-1 and melanoma COLO741 cells, all of which also undergo death when treated with the specific targeted agent. In other cell lines, such as MET-addicted gastric carcinoma MKN45 and EGFR-addicted CRC SW48 lines, where oncogene inhibition only blocked proliferation, HSP27 knockdown made targeted agents switch from cytostatic to cytotoxic activity. Mechanistically, the more the cells were susceptible to HSP27 suppression, the more they were primed for death, as demonstrated by increased levels of mitochondrial outer membrane permeabilization. Priming for death was accompanied by the increase in pro-apoptotic proteins of the BCL2 family and of active caspase-3 and lamin B. Together, these data suggest that oncogene-addicted cells require HSP27 for survival and that HSP27 might interfere with the effectiveness of targeted agents. © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Characterization of tachykinin receptors mediating bronchomotor and vasodepressor responses to neuropeptide gamma and substance P in the anaesthetized rabbit.

PubMed

Yuan, L; Burcher, E; Nail, B S

1998-02-01

The effects of i.v. injections of two endogenous tachykinins, substance P (SP) and neuropeptide gamma and the highly selective tachykinin agonists [Sar9,Met(O2)11]-SP, [Lys5,MeLeu9, Nle10]-NKA(4-10) and senktide, on total lung resistance (RL), dynamic lung compliance (Cdyn) and systemic blood pressure, were compared in the anaesthetized rabbit. Senktide, the NK-3 receptor selective agonist, had no effect on RL, Cdyn or blood pressure. The other four agonists caused dose-dependent increases in RL and Cdyn, with [Sar9,Met(O2)11]-SP being the most potent agonist in producing changes in the absence of phosphoramidon. This suggested that NK-1 receptors play an important role in these responses. [Sar9, Met(O2)11]-SP, SP and neuropeptide gamma also decreased blood pressure. Phosphoramidon (1 mg/kg) potentiated the changes in RL and Cdyn evoked by [Sar9,Met(O2)11]-SP and SP, with very marked enhancement of responses to neuropeptide gamma. Responses to [Lys5, MeLeu9,Nle10]-NKA(4-10) were unaffected, suggesting that this NK-2 selective agonist may not be catabolized by neutral endopeptidase (NEP). In the presence of phosphoramidon, the non-peptide tachykinin NK-1 receptor selective antagonist CP 96345 (80 nmol/kg) reduced all responses to [Sar9,Met(O2)11]-SP and SP, whereas the NK-2 selective antagonist SR 48968 (40 nmol/kg) inhibited the bronchomotor but not the vasodepressor responses to neuropeptide gamma and [Lys5,MeLeu9, Nle10]-NKA(4-10). The fall in blood pressure induced by neuropeptide gamma was diminished by CP 96345, whereas bronchoconstriction was unaffected, indicating possible differences in NK-1 receptors in the vasculature and airways. Electrical stimulation of the distal ends of vagus nerves caused increases in RL which were abolished by atropine (1 mg/kg). Copyright 1998 Academic Press Limited

ATCA/muTCA for Physics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jezynski, Tomasz; /DESY; Larsen, Raymond

ATCA/{mu}TCA platforms are attractive because of the modern serial link architecture, high availability features and many packaging options. Less-demanding availability applications can be met economically by scaling back speed and redundancy. The ATCA specification was originally targeted for the Telecom industry but has gained recently a much wider user audience. The purpose of this paper is to report on present hardware and software R and D efforts where ATCA and {mu}TCA are planned, already being used or in development using selected examples for accelerator and detectors in the Physics community. It will present also the status of a proposal formore » physics extensions to ATCA/{mu}TCA specifications to promote inter-operability of laboratory and industry designs for physics.« less

BDNF Val66Met polymorphism is associated with abnormal interhemispheric transfer of a newly acquired motor skill.

PubMed

Morin-Moncet, Olivier; Beaumont, Vincent; de Beaumont, Louis; Lepage, Jean-Francois; Théoret, Hugo

2014-05-01

Recent data suggest that the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene can alter cortical plasticity within the motor cortex of carriers, which exhibits abnormally low rates of cortical reorganization after repetitive motor tasks. To verify whether long-term retention of a motor skill is also modulated by the presence of the polymorphism, 20 participants (10 Val66Val, 10 Val66Met) were tested twice at a 1-wk interval. During each visit, excitability of the motor cortex was measured by transcranial magnetic stimulations (TMS) before and after performance of a procedural motor learning task (serial reaction time task) designed to study sequence-specific learning of the right hand and sequence-specific transfer from the right to the left hand. Behavioral results showed a motor learning effect that persisted for at least a week and task-related increases in corticospinal excitability identical for both sessions and without distinction for genetic group. Sequence-specific transfer of the motor skill from the right hand to the left hand was greater in session 2 than in session 1 only in the Val66Met genetic group. Further analysis revealed that the sequence-specific transfer occurred equally at both sessions in the Val66Val genotype group. In the Val66Met genotype group, sequence-specific transfer did not occur at session 1 but did at session 2. These data suggest a limited impact of Val66Met polymorphism on the learning and retention of a complex motor skill and its associated changes in corticospinal excitability over time, and a possible modulation of the interhemispheric transfer of procedural learning. Copyright © 2014 the American Physiological Society.

Gauging a Hydrocarbon Ruler by an Intrinsic Exciton Probe†

PubMed Central

Khan, M. Adil; Neale, Chris; Michaux, Catherine; Pomés, Régis; Privé, Gilbert G.; Woody, Robert W.; Bishop, Russell E.

2016-01-01

The structural basis of lipid acyl-chain selection by membrane-intrinsic enzymes is poorly understood because most integral membrane enzymes of lipid metabolism have proven refractory to structure determination; however, robust enzymes from the outer membranes of Gram-negative bacteria are now providing a first glimpse at the underlying mechanisms. The methylene unit resolution of the phospholipid: lipid A palmitoyltransferase PagP is determined by the hydrocarbon ruler, a 16-carbon saturated acyl-chain-binding pocket buried within the transmembrane β-barrel structure. Substitution of Gly88 lining the floor of the hydrocarbon ruler with Ala or Met makes the enzyme select specifically 15- or 12-carbon saturated acyl chains, respectively, indicating that hydrocarbon ruler depth determines acyl-chain selection. However, the Gly88Cys PagP resolution does not diminish linearly because it selects both 14- and 15-carbon saturated acyl chains. We discovered that an exciton, emanating from a buried Tyr26–Trp66 phenol–indole interaction, is extinguished by a local structural perturbation arising from the proximal Gly88Cys PagP sulfhydryl group. Site-specific S-methylation of the single Cys afforded Gly88Cys-S-methyl PagP, which reasserted both the exciton and methylene unit resolution by specifically selecting 13-carbon saturated acyl chains for transfer to lipid A. Unlike the other Gly88 substitutions, the Cys sulfhydryl group recedes from the hydrocarbon ruler floor and locally perturbs the subjacent Tyr26 and Trp66 aromatic rings. The resulting hydrocarbon ruler expansion thus occurs at the exciton’s expense and accommodates an extra methylene unit in the selected acyl chain. The hydrocarbon ruler–exciton juxtaposition endows PagP with a molecular gauge for probing the structural basis of lipid acyl-chain selection in a membrane-intrinsic environment. PMID:17375935

Metabolic syndrome impairs reactivity and wall mechanics of cerebral resistance arteries in obese Zucker rats.

PubMed

Brooks, Steven D; DeVallance, Evan; d'Audiffret, Alexandre C; Frisbee, Stephanie J; Tabone, Lawrence E; Shrader, Carl D; Frisbee, Jefferson C; Chantler, Paul D

2015-12-01

The metabolic syndrome (MetS) is highly prevalent in the North American population and is associated with increased risk for development of cerebrovascular disease. This study determined the structural and functional changes in the middle cerebral arteries (MCA) during the progression of MetS and the effects of chronic pharmacological interventions on mitigating vascular alterations in obese Zucker rats (OZR), a translationally relevant model of MetS. The reactivity and wall mechanics of ex vivo pressurized MCA from lean Zucker rats (LZR) and OZR were determined at 7-8, 12-13, and 16-17 wk of age under control conditions and following chronic treatment with pharmacological agents targeting specific systemic pathologies. With increasing age, control OZR demonstrated reduced nitric oxide bioavailability, impaired dilator (acetylcholine) reactivity, elevated myogenic properties, structural narrowing, and wall stiffening compared with LZR. Antihypertensive therapy (e.g., captopril or hydralazine) starting at 7-8 wk of age blunted the progression of arterial stiffening compared with OZR controls, while treatments that reduced inflammation and oxidative stress (e.g., atorvastatin, rosiglitazone, and captopril) improved NO bioavailability and vascular reactivity compared with OZR controls and had mixed effects on structural remodeling. These data identify specific functional and structural cerebral adaptations that limit cerebrovascular blood flow in MetS patients, contributing to increased risk of cognitive decline, cerebral hypoperfusion, and ischemic stroke; however, these pathological adaptations could potentially be blunted if treated early in the progression of MetS. Copyright © 2015 the American Physiological Society.

An Investigation of Instantaneous Plume Rise from Rocket Exhaust

DTIC Science & Technology

1996-12-01

METERS) TOP = 2973.48 BASE= 210.62 SIGMAR (AZ) AT THE SURFACE (DEGREES) 13.5054 SIGMER(EL) AT THE SURFACE (DEGREES) 2.9738 MET. WIND WIND LAYER WIND SPEED...SELECTED LAYER HEIGHT- (METERS) TOP = 2973.48 BASE= 210.62 SIGMAR (AZ) AT THE SURFACE (DEGREES) 13.6911 SIGMER(EL) AT THE SURFACE (DEGREES) 2.9738 MET...TIME (SECS) 368.08 FIRST MIXING LAYER HEIGHT- (METERS) TOP = 210.62 BASE= 0.00 SECOND SELECTED LAYER HEIGHT- (METERS) TOP = 2973.48 BASE= 210.62 SIGMAR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dale, Virginia H.; Efroymson, Rebecca Ann; Kline, Keith L.

A framework for selecting and evaluating indicators of bioenergy sustainability is presented. This framework is designed to facilitate decision-making about which indicators are useful for assessing sustainability of bioenergy systems and supporting their deployment. Efforts to develop sustainability indicators in the United States and Europe are reviewed. The first steps of the framework for indicator selection are defining the sustainability goals and other goals for a bioenergy project or program, gaining an understanding of the context, and identifying the values of stakeholders. From the goals, context, and stakeholders, the objectives for analysis and criteria for indicator selection can be developed.more » The user of the framework identifies and ranks indicators, applies them in an assessment, and then evaluates their effectiveness, while identifying gaps that prevent goals from being met, assessing lessons learned, and moving toward best practices. The framework approach emphasizes that the selection of appropriate criteria and indicators is driven by the specific purpose of an analysis. Realistic goals and measures of bioenergy sustainability can be developed systematically with the help of the framework presented here.« less

Fatty Acid Synthase Activity as a Target for c-Met Driven Prostate Cancer

DTIC Science & Technology

2013-07-01

to aid future studies. Identification is a highly significant finding with regard to the potential for future therapeutic development targeted at...Met trafficking, stability, and ultimately oncogenic potential . Palmitoylation defective mutants will be used in animal models of c-Met driven tumor...growth (Aim 2). In addition, future work toward identifying the enzyme responsible for palmitoylation of c- Met will provide a new specific target

Discovery of potent 1H-imidazo[4,5-b]pyridine-based c-Met kinase inhibitors via mechanism-directed structural optimization.

PubMed

An, Xiao-De; Liu, Hongyan; Xu, Zhong-Liang; Jin, Yi; Peng, Xia; Yao, Ying-Ming; Geng, Meiyu; Long, Ya-Qiu

2015-02-01

Starting from our previously identified novel c-Met kinase inhibitors bearing 1H-imidazo[4,5-h][1,6]naphthyridin-2(3H)-one scaffold, a global structural exploration was conducted to furnish an optimal binding motif for further development, directed by the enzyme inhibitory mechanism. First round SAR study picked two imidazonaphthyridinone frameworks with 1,8- and 3,5-disubstitution pattern as class I and class II c-Met kinase inhibitors, respectively. Further structural optimization on type II inhibitors by truncation of the imidazonaphthyridinone core and incorporation of an N-phenyl cyclopropane-1,1-dicarboxamide pharmacophore led to the discovery of novel imidazopyridine-based c-Met kinase inhibitors, displaying nanomolar enzyme inhibitory activity and improved Met kinase selectivity. More significantly, the new chemotype c-Met kinase inhibitors effectively inhibited Met phosphorylation and its downstream signaling as well as the proliferation of Met-dependent EBC-1 human lung cancer cells at submicromolar concentrations. Copyright © 2014 Elsevier Ltd. All rights reserved.

Prevalence and correlates of metabolic syndrome in pre-crisis Syria: call for current relief efforts.

PubMed

Ramadan, H; Naja, F; Fouad, F M; Antoun, E; Jaffa, M; Chaaban, R; Haidar, M; Sibai, A M

2016-12-12

This study aimed to assess the prevalence, components and correlates of metabolic syndrome (MetS) in adults in pre-crisis Aleppo, Syrian Arab Republic. We used a population-based, 2-stage cluster sampling method in a population of 557 men and 611 women, randomly selected from 83 residential neighbourhoods including many rural settlers. Sociodemographic and lifestyle characteristics, comorbidity, anthropometry and biochemical indices were measured. Prevalence of MetS was estimated at 39.6%, with comparable rates in men and women. Hypertension was the most prevalent component (56.6%), followed by central obesity (51.4%). Among women, education (12 years) was inversely associated with risk of MetS, while family history of obesity and diabetes was associated with an increased risk. The high prevalence of MetS and its components emphasizes the burden of cardiovascular diseases among adults in pre-crisis Aleppo. A system of surveillance and management for cardiovascular diseases needs to be incorporated into the current humanitarian response.

Energy cost of physical activities in 12-y-old girls: MET values and the influence of body weight.

PubMed

Spadano, J L; Must, A; Bandini, L G; Dallal, G E; Dietz, W H

2003-12-01

Few data exist on the energy cost of specific activities in children. The influence of body weight on the energy cost of activity when expressed as metabolic equivalents (METs) has not been vigorously explored. To provide MET data on five specific activities in 12-y-old girls and to test the hypothesis that measured MET values are independent of body weight. In 17 12-y-old girls, resting metabolic rate (RMR) and the energy expended while sitting, standing, walking on a flat treadmill at 3.2 and at 4.8 km/h, and walking on a treadmill at a 10% incline at 4.8 km/h were measured using indirect calorimetry. MET values were calculated by dividing the energy expenditure of an activity by the subject's RMR. The influence of body weight was assessed using simple linear regression. The observed METs were more consistent with published values for similar activities in adults than those offered for children. Body weight was a statistically significant predictor of the MET of all three walking activities, but not the MET of sitting or standing. Body weight explained 25% of the variance in the MET value for walking at 3.2 km/h, 39% for walking at 4.8 km/h, and 63% for walking at a 10% incline at 4.8 km/h. METs for the three walking activities were not independent of body weight. The use of average MET values to estimate the energy cost of these three activities would result in an underestimation of their energy cost in heavier girls and an overestimation in lighter girls. These results suggest that the estimation of total energy expenditure from activity diary, recall, and direct observation data using average MET values may be biased by body weight.

Characterization of a human antigen specific helper factor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Richardson, B.

1986-03-01

While antigen (Ag) specific helper factors have been characterized in mice, similar molecules have not been identified in humans. To characterize human antigen specific helper molecules, an IL-2 dependent tetanus toxoid (T.T.) reactive T cell line was fused with a 6-thioguanine resistant CEM line, and hybrids selected in medium containing hypoxanthine and azaserine. Hybrids were screened by culturing the cells with /sup 35/S-Met then reacting the supernatants with T.T. or hepatitis vaccine immobilized on nitrocellulose. One hybrid, TT6BA-O, was identified which secreted a Met-containing molecule which bound T.T. but not hepatitis vaccine. Supernatants from TT6BA-O, but not the parent CEMmore » line, when added to autologous peripheral blood mononuclear cells (PBMC's) stimulated secretion of T.T. specific antibodies (Abs). Specificity controls demonstrated that TT6BA-O supernatant did not induce antibodies to diphtheria toxoid, hepatitis vaccine or pneumococcal polysaccharide, and total immunoglobulin (lg) synthesis was minimally increased. In contrast, pokeweed mitogen stimulated significant lg synthesis as well as Ab's to pneumococcal polysaccharide and T.T. TT6BA-O supernatant induced anti-T.T.Ab's in autologous PBMC's but not PBMC's from 3 unrelated donors, suggesting that the activity of the helper factor is restricted, possibly by the MHC. The molecular weight of the helper factor was estimated at 100,000-150,000 by Sephacryl S-300 chromatography. Finally, the helper factor could be demonstrated to bind and elute from sephorose-immobilized T.T. and anti-DR antisera, but not anti-lg antisera or the T40/25 monoclonal antibody, which binds a nonpolymorphic determinant on the human T cell receptor. These results demonstrate that human Ag specific helper factors exist, bind antigen and bear class II MHC determinants.« less

Optimal definitions for abdominal obesity and the metabolic syndrome in Andean Hispanics: the PREVENCION study.

PubMed

Medina-Lezama, Josefina; Pastorius, Catherine A; Zea-Diaz, Humberto; Bernabe-Ortiz, Antonio; Corrales-Medina, Fernando; Morey-Vargas, Oscar Leopoldo; Chirinos, Diana Andrea; Muñoz-Atahualpa, Edgar; Chirinos-Pacheco, Julio; Chirinos, Julio Alonso

2010-06-01

We aimed to establish optimal definitions for abdominal obesity and metabolic syndrome (MetS) among Andean adults. Among 1,448 Andean adults, we assessed the relationship between waist circumference and subclinical vascular disease assessed by carotid intima-media thickness (cIMT) and manifest cardiovascular disease (M-CVD). Optimal waist circumference cutoffs to classify individuals with abnormal cIMT or M-CVD were >97 and >87 cm in men and women, respectively. With these cutoffs, there was substantial disagreement between the original American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI) and the recently updated MetS definition, particularly among men (kappa = 0.85). Subjects with MetS identified by the updated definition but not meeting the original AHA/NHLBI MetS criteria demonstrated significantly increased cIMT (P < 0.001) compared with subjects who did not meet the MetS criteria by either definition. Our findings support the use of ethnic-specific waist circumference cutoffs and the updated MetS definition in Andean adults.

Acquired MET D1228V mutation and resistance to MET inhibition in lung cancer

PubMed Central

Bahcall, Magda; Sim, Taebo; Paweletz, Cloud P.; Patel, Jyoti D.; Alden, Ryan S.; Kuang, Yanan; Sacher, Adrian G.; Kim, Nam Doo; Lydon, Christine A.; Awad, Mark M.; Jaklitsch, Michael T.; Sholl, Lynette M.; Jänne, Pasi A.; Oxnard, Geoffrey R.

2016-01-01

Amplified and/or mutated MET can act as both a primary oncogenic driver and as a promoter of tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC). However, the landscape of MET-specific targeting agents remains underdeveloped and understanding of mechanisms of resistance to MET TKIs is limited. Here we present a case of a patient with lung adenocarcinoma harboring both a mutation in EGFR and an amplification of MET, who after progression on erlotinib, responded dramatically to combined MET and EGFR inhibition with savolitinib and osimertinib. When resistance developed to this combination, a new MET kinase domain mutation, D1228V, was detected. Our in vitro findings demonstrate that MET D1228V induces resistance to type I MET TKIs through impaired drug binding while sensitivity to type II MET TKIs is maintained. Based on these findings, the patient was treated with erlotinib combined with cabozantinib, a type II MET inhibitor, and exhibited a response. PMID:27694386

c-Met–mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma

PubMed Central

Huang, Menggui; Liu, Tianrun; Ma, Peihong; Mitteer, R. Alan; Zhang, Zhenting; Kim, Hyun Jun; Yeo, Eujin; Zhang, Duo; Cai, Peiqiang; Li, Chunsheng; Zhang, Lin; Zhao, Botao; Roccograndi, Laura; O’Rourke, Donald M.; Dahmane, Nadia; Gong, Yanqing; Koumenis, Constantinos

2016-01-01

Aberrant vascularization is a hallmark of cancer progression and treatment resistance. Here, we have shown that endothelial cell (EC) plasticity drives aberrant vascularization and chemoresistance in glioblastoma multiforme (GBM). By utilizing human patient specimens, as well as allograft and genetic murine GBM models, we revealed that a robust endothelial plasticity in GBM allows acquisition of fibroblast transformation (also known as endothelial mesenchymal transition [Endo-MT]), which is characterized by EC expression of fibroblast markers, and determined that a prominent population of GBM-associated fibroblast-like cells have EC origin. Tumor ECs acquired the mesenchymal gene signature without the loss of EC functions, leading to enhanced cell proliferation and migration, as well as vessel permeability. Furthermore, we identified a c-Met/ETS-1/matrix metalloproteinase–14 (MMP-14) axis that controls VE-cadherin degradation, Endo-MT, and vascular abnormality. Pharmacological c-Met inhibition induced vessel normalization in patient tumor–derived ECs. Finally, EC-specific KO of Met inhibited vascular transformation, normalized blood vessels, and reduced intratumoral hypoxia, culminating in suppressed tumor growth and prolonged survival in GBM-bearing mice after temozolomide treatment. Together, these findings illustrate a mechanism that controls aberrant tumor vascularization and suggest that targeting Endo-MT may offer selective and efficient strategies for antivascular and vessel normalization therapies in GBM, and possibly other malignant tumors. PMID:27043280

RNase MRP Cleaves Pre-tRNASer-Met in the tRNA Maturation Pathway

PubMed Central

Adachi, Kousuke; Nobe, Yuko; Kobayashi, Junya; Hirota, Kouji; Oliveira, Douglas V.; Taoka, Masato; Isobe, Toshiaki

2014-01-01

Ribonuclease mitochondrial RNA processing (RNase MRP) is a multifunctional ribonucleoprotein (RNP) complex that is involved in the maturation of various types of RNA including ribosomal RNA. RNase MRP consists of a potential catalytic RNA and several protein components, all of which are required for cell viability. We show here that the temperature-sensitive mutant of rmp1, the gene for a unique protein component of RNase MRP, accumulates the dimeric tRNA precursor, pre-tRNASer-Met. To examine whether RNase MRP mediates tRNA maturation, we purified the RNase MRP holoenzyme from the fission yeast Schizosaccharomyces pombe and found that the enzyme directly and selectively cleaves pre-tRNASer-Met, suggesting that RNase MRP participates in the maturation of specific tRNA in vivo. In addition, mass spectrometry–based ribonucleoproteomic analysis demonstrated that this RNase MRP consists of one RNA molecule and 11 protein components, including a previously unknown component Rpl701. Notably, limited nucleolysis of RNase MRP generated an active catalytic core consisting of partial mrp1 RNA fragments, which constitute “Domain 1” in the secondary structure of RNase MRP, and 8 proteins. Thus, the present study provides new insight into the structure and function of RNase MRP. PMID:25401760

A new Infrared Atmospheric Sounding Interferometer channel selection and assessment of its impact on Met Office NWP forecasts

NASA Astrophysics Data System (ADS)

Noh, Young-Chan; Sohn, Byung-Ju; Kim, Yoonjae; Joo, Sangwon; Bell, William; Saunders, Roger

2017-11-01

A new set of Infrared Atmospheric Sounding Interferometer (IASI) channels was re-selected from 314 EUMETSAT channels. In selecting channels, we calculated the impact of the individually added channel on the improvement in the analysis outputs from a one-dimensional variational analysis (1D-Var) for the Unified Model (UM) data assimilation system at the Met Office, using the channel score index (CSI) as a figure of merit. Then, 200 channels were selected in order by counting each individual channel's CSI contribution. Compared with the operationally used 183 channels for the UM at the Met Office, the new set shares 149 channels, while the other 51 channels are new. Also examined is the selection from the entropy reduction method with the same 1D-Var approach. Results suggest that channel selection can be made in a more objective fashion using the proposed CSI method. This is because the most important channels can be selected across the whole IASI observation spectrum. In the experimental trial runs using the UM global assimilation system, the new channels had an overall neutral impact in terms of improvement in forecasts, as compared with results from the operational channels. However, upper-tropospheric moist biases shown in the control run with operational channels were significantly reduced in the experimental trial with the newly selected channels. The reduction of moist biases was mainly due to the additional water vapor channels, which are sensitive to the upper-tropospheric water vapor.

HIF evaluation of In-Situ Aqua TROLL 400

USGS Publications Warehouse

Tillman, Evan F.

2017-10-18

The In-Situ Aqua TROLL 400 (Aqua TROLL 400) was tested at the U.S. Geological Survey (USGS) Hydrologic Instrumentation Facility (HIF) against known standards over the Aqua TROLL 400’s operating temperature to verify the manufacturer’s stated accuracy specifications and the USGS recommendations for pH, dissolved oxygen (DO), and specific conductance (SC). The Aqua TROLL 400 manufacturer’s specifications are within the USGS recommendations for all parameters tested, except for DO, which is outside the USGS recommendation at DO concentrations of 8.0 milligrams per liter (mg/L) and higher. The Aqua TROLL 400 was compliant with Serial Digital Interface at 1200 baud (SDI-12) version 1.3. During laboratory testing of pH, the Aqua TROLL 400 sonde met the U.S. Geological Survey “National Field Manual for the Collection of Water-Quality Data” (NFM) recommendations for pH at all values tested, except at 4 degrees Celsius (°C) at pH 9.395 and pH 3.998. The Aqua TROLL 400 met the manufacturer specifications for pH at all values tested, except for pH buffers 3.998, 9.395, and 10.245 at 4 °C; pH 2.990 and 3.998 at 15 °C; and pH 3.040 at 40 °C. The Aqua TROLL 400 met the NFM recommendations at 93.7 percent of the SC values tested and met the manufacturer’s accuracy specifications at 56.3 percent of the SC values tested. During the laboratory testing for DO, the Aqua TROLL 400 met the manufacturer specifications, except at 5.55 mg/L, and met the NFM recommendations at all concentrations tested. An Aqua TROLL 400 was field tested at USGS Station 02492620, National Space Technology Laboratories (NSTL) Station, Mississippi, on the Pearl River for 6 weeks and showed good agreement with the well-maintained site sonde data for pH, DO, temperature, and SC.

Synthesis and positron emission tomographic (PET) baboon studies of [{sup 11}C]methadone and R-(-)-[{sup 11}C]methandone

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ding, Y.S.; Fowler, J.S.; Volkow, N.D.

1996-05-01

Methadone (MET) maintenance has been used successfully for many years in the rehabilitation of heroin addicts. MET, a typical m{mu}-opioid receptor agonist, exists as two enantiomers and is used clinically as the racemic mixture. However, R-(-)-MET has a 10-fold higher affinity for m{mu} receptors than S-(+)-MET (IC{sub 50}: 3.0 nM and 26.4 nM, respectively) and R-(-)-MET is almost entirely responsible for the therapeutic actions of the racemate. In order to examine the pharmacokinetics and stereoselectivity of the drug, we have synthesized both [{sup 11}C]MET and R-(-)-[{sup 11}C]MET. Preparing the precursor by one-step approach to the N-demethylated methadone was precluded asmore » other investigators cited problems with intramolecular cyclization. Therefore, a four-step synthesis using MET (or R-(-)-MET) as starting material was required to obtain the precursor, followed by a two-step radiolabeling synthesis (N-methylation followed by oxidation) to obtain [{sup 11}C]MET (or R-(-)-[{sup 11}C]MET). Comparative PET studies in the same baboon showed peak striatal uptake was 0.022%/cc at 5 minutes with a half time of clearance from peak of 100 minutes for R-(-)-[{sup 11}C]MET and a peak uptake of 0.013%/cc with a half time of 90 min for [{sup 11}C]MET. R-(-)-[{sup 11}C]MET also showed a slower disappearance in plasma. Both tracers showed higher C-11 in basal ganglia (BG), thalamus and midbrain relative to the cerebellum (CB) and occipital cortex (OC) but the BG/OC ratio was higher for R-(-)-[{sup 11}C]MET (1.3 vs 1.1). Pretreatment with naloxone (1 mg/kg, iv) increased R-(-)-[{sup 11}C]MET uptake in all brain regions whereas unlabeled MET slightly increased C-11 clearance in BG, OC and CB. These initial results show higher brain concentration and specificity of the pharmacologically active enantiomer of methadone along with significant non-specific binding.« less

Early-life nutritional status and metabolic syndrome: gender-specific associations from a cross-sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).

PubMed

Briskiewicz, Bruna Lucas; Barreto, Sandhi Maria; do Amaral, Joana Ferreira; Diniz, Maria de Fátima Haueisen Sander; Molina, Maria Del Carmen Bisi; Matos, Sheila Maria Alvim; Cardoso, Letícia de Oliveira; Velasquez-Melendez, Gustavo; Schmidt, Maria Inês; Giatti, Luana

2018-06-01

In the present study we investigated gender-specific associations of low birth weight (LBW) and shorter relative leg length with metabolic syndrome (MetS) after adjusting for sociodemographic characteristics and health-related behaviours. We also investigated whether these associations are independent of age at menarche and BMI at 20 years old. Cross-sectional analysis. Baseline data from 12 602 participants (35-74 years) of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), 2008-2010. MetS was defined according to the revised National Cholesterol Education Program Adult Treatment Panel III guidelines. LBW (<2·5 kg) and age- and sex-standardized relative leg length (high, medium and low) were the explanatory variables studied. The strength of the associations between the explanatory variables and MetS was estimated by Poisson regression with robust variance. MetS prevalence was 34·2 %; it was more prevalent in men (36·8 %) than in women (32·2 %). In multivariate analysis, LBW was associated (prevalence ratio; 95 % CI) with MetS only in women (1·28; 1·24, 1·45). Shorter leg length was associated with MetS in both men (1·21; 1·09, 1·35 and 1·46; 1·29, 1·65 for low and medium lengths, respectively) and women (1·12; 1·00, 1·25 and 1·40; 1·22, 1·59 for low and medium lengths, respectively). Additional adjustments for age at menarche and BMI at 20 years old did not change the associations. Poor nutritional status as estimated by LBW and lower leg length in childhood was associated with a higher prevalence of MetS, although LBW was a significant factor only among women.

Metabolic syndrome parameters in adolescents may be determinants for the future periodontal diseases.

PubMed

Lee, Kyeong-Soo; Lee, Sang Gyu; Kim, Eun-Kyong; Jin, Hye-Jung; Im, Sang-Uk; Lee, Hee-Kyung; Merchant, Anwar T; Song, Keun-Bae; Choi, Youn-Hee

2015-02-01

The prevalence of metabolic syndrome (MetS) increases even in adolescents. The evidence that MetS is associated with the periodontal diseases in adolescents has been understudied. Therefore, our aim was to assess the association between MetS parameters and gingivitis in adolescents. A total of 941 participants (590 boys, 351 girls), aged 12-18 years was selected from the Fourth Korea National Health and Nutrition Examination Survey, a cross-sectional and nationally representative survey, which had had information on waist circumference, blood pressure, serum triglyceride, high-density lipoprotein (HDL) cholesterol, and the fasting blood sugar and community periodontal Index (CPI). The number of positive parameters of MetS showed significant positive correlation with gingivitis; adjusted and crude ORs with one positive parameters of MetS were 1.92 (95% CI: 1.21-3.04) and 1.88(95% CI: 1.28-2.76), respectively. And adjusted OR with three or more positive parameters of MetS was 3.29 (95% CI: 1.24-8.71). Among five parameters of MetS, Low HDL-cholesterol showed significant association with gingivitis (crude OR 2.12, 95% CI 1.20-3.73; adjusted OR 1.96, 95% CI 1.24-3.12). Having more positive parameters of MetS and low HDL-cholesterol parameter had an independent relationship with the prevalence of gingivitis, which may be determinants for the future periodontal diseases even in adolescents. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Metabolic syndrome and low high-density lipoprotein cholesterol are associated with adverse pathological features in patients with prostate cancer treated by radical prostatectomy.

PubMed

Lebdai, Souhil; Mathieu, Romain; Leger, Julie; Haillot, Olivier; Vincendeau, Sébastien; Rioux-Leclercq, Nathalie; Fournier, Georges; Perrouin-Verbe, Marie-Aimée; Doucet, Laurent; Azzouzi, Abdel Rahmene; Rigaud, Jérome; Renaudin, Karine; Charles, Thomas; Bruyere, Franck; Fromont, Gaelle

2018-02-01

Previous studies have suggested a link between metabolic syndrome (MetS) and prostate cancer (PCa). In the present study, we aimed to assess the association between MetS and markers of PCa aggressiveness on radical prostatectomy (RP). All patients consecutively treated for PCa by RP in 6 academic institutions between August 2013 and July 2016 were included. MetS was defined as at least 3 of 5 components (obesity, elevated blood pressure, diabetes, low high-density lipoprotein (HDL)-cholesterol, and hypertriglyceridemia). Demographic, biological, and clinical parameters were prospectively collected, including: age, biopsy results, preoperative serum prostate-specific antigen, surgical procedure, and pathological data of RP specimen. Locally advanced disease was defined as a pT-stage ≥3. International Society of Urological Pathology (ISUP) groups were used for pathological grading. Qualitative and quantitative variables were compared using chi-square and Wilcoxon tests; logistic regression analyses assessed the association of MetS and its components with pathological data. Statistical significance was defined as a P<0.05. Among 567 men, 249 (44%) had MetS. In a multivariate model including preoperative prostate-specific antigen, biopsy ISUP-score, clinical T-stage, age, and ethnicity: we found that MetS was an independent risk factor for positive margins, and ISUP group ≥4 on the RP specimen (odds ratio [OR] = 1.5; 95% CI: 1.1-2.3; P = 0.035; OR = 2.0; 95% CI: 1.1-4.0; P = 0.044, respectively). In addition, low HDL-cholesterol level was associated with locally advanced PCa (OR = 1.6; 95% CI: 1.1-2.4; P = 0.024). Risks of adverse pathological features increased with the number of MetS components: having ≥ 4 MetS components was significantly associated with higher risk of ISUP group ≥ 4 and higher risk of positive margins (OR = 1.9; 95% CI: 1.1-3.3; P = 0.017; OR = 1.8; 95% CI: 1.1-2.8; P = 0.007, respectively). MetS was an independent predictive factor for higher ISUP group and positive margins at RP. Low HDL-cholesterol alone, and having 4 and more MetS components were also associated with higher risk of adverse pathological features. Copyright © 2018. Published by Elsevier Inc.

The Association between Breakfast Skipping and Body Weight, Nutrient Intake, and Metabolic Measures among Participants with Metabolic Syndrome

PubMed Central

Zhang, Lijuan; Cordeiro, Lorraine S.; Liu, Jinghua; Ma, Yunsheng

2017-01-01

The effect of skipping breakfast on health, especially in adults, remains a controversial topic. A secondary data analysis was conducted to examine associations between breakfast eating patterns and weight loss, nutrient intake, and metabolic parameters among participants with metabolic syndrome (MetS) (n = 240). Three randomly selected 24-h dietary recalls were collected from each participant at baseline and at the one-year visit. Skipped breakfast was seen in 32.9% at baseline and in 17.4% at the one-year visit, respectively. At baseline, after adjustment for demographics and physical activity, participants who ate breakfast had a higher thiamin, niacin, and folate intake than did breakfast skippers (p < 0.05); other selected parameters including body weight, dietary quality scores, nutrient intake, and metabolic parameters showed no significant differences between the two groups (p ≥ 0.05). From baseline to one year, after adjustment for covariates, mean fat intake increased by 2.7% (95% confidence intervals (CI): −1.0, 6.5%) of total energy in breakfast skippers in comparison to the 1.2% decrease observed in breakfast eaters (95% CI: −3.4, 1.1%) (p = 0.02). Mean changes in other selected parameters showed no significant differences between breakfast skippers and eaters (p > 0.05). This study did not support the hypothesis that skipping breakfast has impact on body weight, nutrient intakes, and selected metabolic measures in participants with MetS. PMID:28420112

Development of a 3D Tissue Culture-Based High-Content Screening Platform That Uses Phenotypic Profiling to Discriminate Selective Inhibitors of Receptor Tyrosine Kinases.

PubMed

Booij, Tijmen H; Klop, Maarten J D; Yan, Kuan; Szántai-Kis, Csaba; Szokol, Balint; Orfi, Laszlo; van de Water, Bob; Keri, Gyorgy; Price, Leo S

2016-10-01

3D tissue cultures provide a more physiologically relevant context for the screening of compounds, compared with 2D cell cultures. Cells cultured in 3D hydrogels also show complex phenotypes, increasing the scope for phenotypic profiling. Here we describe a high-content screening platform that uses invasive human prostate cancer cells cultured in 3D in standard 384-well assay plates to study the activity of potential therapeutic small molecules and antibody biologics. Image analysis tools were developed to process 3D image data to measure over 800 phenotypic parameters. Multiparametric analysis was used to evaluate the effect of compounds on tissue morphology. We applied this screening platform to measure the activity and selectivity of inhibitors of the c-Met and epidermal growth factor (EGF) receptor (EGFR) tyrosine kinases in 3D cultured prostate carcinoma cells. c-Met and EGFR activity was quantified based on the phenotypic profiles induced by their respective ligands, hepatocyte growth factor and EGF. The screening method was applied to a novel collection of 80 putative inhibitors of c-Met and EGFR. Compounds were identified that induced phenotypic profiles indicative of selective inhibition of c-Met, EGFR, or bispecific inhibition of both targets. In conclusion, we describe a fully scalable high-content screening platform that uses phenotypic profiling to discriminate selective and nonselective (off-target) inhibitors in a physiologically relevant 3D cell culture setting. © 2016 Society for Laboratory Automation and Screening.

Thiamine and its phosphate esters in relation to cardiometabolic risk factors in Saudi Arabs

PubMed Central

2013-01-01

Background Thiamine deficiency has suggested to be linked to several insulin-resistance complications. In this study, we aim to associate circulating thiamine levels among cardiometabolic parameters in an Arab cohort using a simple, sensitive, rapid and selective high-performance liquid chromatography (HPLC) method that has recently been developed. Methods A total of 236 randomly selected, consenting Saudi adult participants (166 males and 70 females) were recruited and screened for the presence of the metabolic syndrome (MetS) using the modified National Cholesterol Education Program–Adult Treatment Panel III definition. Blood thiamine and its derivatives were quantified using HPLC. Results A total of 140 participants (53.9%) had MetS. The levels of thiamine and its derivatives of those with MetS were not significantly different from those without. However, hypertensive subjects had significantly higher urinary thiamine (P = 0.03) as well as significantly lower levels of thiamine diphosphate (TDP) (P = 0.01) and total thiamine (P = 0.02) than the normotensive subjects, even after adjusting for age and body mass index (BMI). Furthermore, age- and BMI-matched participants with elevated blood glucose levels had significantly lower levels of thiamine monophosphate (P = 0.020), TDP (P < 0.001) and total thiamine (P < 0.001) and significantly elevated levels of urinary thiamine (P = 0.005) compared to normoglycemic participants. Conclusions Low thiamine levels are associated with elevated blood glucose and hypertension in Saudi adults. Determination of thiamine status may be considered and corrected among patients with, or at high risk for, MetS, but the question whether thiamine deficiency correction translates to improved cardiometabolic status needs further longitudinal investigation. PMID:24059534

Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET

PubMed Central

Peinado, Héctor; Alečković, Maša; Lavotshkin, Simon; Matei, Irina; Costa-Silva, Bruno; Moreno-Bueno, Gema; Hergueta-Redondo, Marta; Williams, Caitlin; García-Santos, Guillermo; Nitadori-Hoshino, Ayuko; Hoffman, Caitlin; Badal, Karen; Garcia, Benjamin A.; Callahan, Margaret K.; Yuan, Jianda; Martins, Vilma R.; Skog, Johan; Kaplan, Rosandra N.; Brady, Mary S.; Wolchok, Jedd D.; Chapman, Paul B.; Kang, Yibin; Bromberg, Jacqueline; Lyden, David

2013-01-01

Tumor-derived exosomes are emerging mediators of tumorigenesis with tissue-specific addresses and messages. We explored the function of melanoma-derived exosomes in the formation of primary tumor and metastases in mouse and human subjects. Exosomes from highly metastatic melanoma increased the metastatic behavior of primary tumors by permanently “educating” bone marrow (BM) progenitors via the MET receptor. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites, and reprogrammed BM progenitors towards a c-Kit+Tie2+Met+ pro-vasculogenic phenotype. Reducing Met expression in exosomes diminished the pro-metastatic behavior of BM cells. Importantly, MET expression was elevated in circulating CD45−C-KITlow/+TIE2+ BM progenitors from metastatic melanoma subjects. RAB1a, RAB5b, RAB7, and RAB27a were highly expressed in melanoma cells and Rab27a RNA interference decreased exosome production, preventing BM education, tumor growth and metastasis. Finally, we identified an exosome-specific “melanoma signature” with prognostic and therapeutic potential, comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. PMID:22635005

Gender Differences in the Effects of the Frequency of Physical Activity on the Incidence of Metabolic Syndrome: Results from a Middle-Aged Community Cohort in Taiwan.

PubMed

Chen, Sheng-Pyng; Chang, Huan-Cheng; Hsiao, Tien-Mu; Yeh, Chih-Jung; Yang, Hao-Jan

2018-06-01

Little is known about how the frequency of physical activity in adults influences the occurrence of metabolic syndrome (MetS), and whether there are gender differences within these effects. In this study, 3368 residents from the established "Landseed Cohort" underwent three waves of health examinations, and those who did not have MetS at baseline were selected and analyzed using a multiple Poisson regression model. By calculating the adjusted relative risk (ARR), the linear and nonlinear relationships between the frequency of physical activity and risk of developing MetS were examined for male and female participants. The prevalence of MetS was fairly stable across the three waves (ranging from 16.24% to 16.82%), but the incidence dropped from 7.11% to 4.52%. The risk of MetS in women was 10 times higher than that in men (ARR = 10.06; 95% CI = 6.60-15.33), and frequent exercise was shown to help prevent it. The frequency of exercise had a linear dose-response effect in females and an exponential protective effect in males on the occurrence of MetS. Exercising more than four times a week for females and twice or more a week for males effectively reduced the risk of developing MetS. The frequency of physical activity in adults was negatively related to the risk of developing MetS, and this relationship differed based on gender. The protective effect of physical activity on MetS was linear in females and exponential in males.

C-reactive Protein Is Associated With Prevalence of the Metabolic Syndrome, Hypertension, and Diabetes Mellitus in US Adults.

PubMed

Mazidi, Mohsen; Toth, Peter P; Banach, Maciej

2018-05-01

The prevalence of metabolic syndrome (MetS) has increased globally and is associated with an increased risk of cardiovascular diseases that may be related to its association with inflammation. We have assessed whether the prevalence of the MetS correlates with a serum high-sensitivity C-reactive protein (hsCRP) concentration in a population-based sample of US men and women. Participants were selected from the US National Health and Nutrition Examination Survey from 2005 to 2010. Of the 17 689 participants analyzed, 8607 (48.3%) were men. The mean age was 45.8 years in the overall sample (between men and women P = .047). The prevalence of MetS, diabetes mellitus, and hypertension increased across quartiles for hsCRP (all P < .001). Moreover, we found that for the age-, race-, sex-, and smoking-adjusted logistic regression, with increasing hsCRP, the risk of having MetS increased with an odds ratio of 5.20 (95% confidence interval, 4.54-5.93, P < .001) when comparing the highest quartile of serum hsCRP with the lowest. This study provides further evidence for an association between MetS and subclinical inflammation.

21 CFR 111.75 - What must you do to determine whether specifications are met?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 2 2010-04-01 2010-04-01 false What must you do to determine whether specifications are met? 111.75 Section 111.75 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION CURRENT GOOD MANUFACTURING PRACTICE IN...

A framework for selecting indicators of bioenergy sustainability

DOE PAGES

Dale, Virginia H.; Efroymson, Rebecca Ann; Kline, Keith L.; ...

2015-05-11

A framework for selecting and evaluating indicators of bioenergy sustainability is presented. This framework is designed to facilitate decision-making about which indicators are useful for assessing sustainability of bioenergy systems and supporting their deployment. Efforts to develop sustainability indicators in the United States and Europe are reviewed. The first steps of the framework for indicator selection are defining the sustainability goals and other goals for a bioenergy project or program, gaining an understanding of the context, and identifying the values of stakeholders. From the goals, context, and stakeholders, the objectives for analysis and criteria for indicator selection can be developed.more » The user of the framework identifies and ranks indicators, applies them in an assessment, and then evaluates their effectiveness, while identifying gaps that prevent goals from being met, assessing lessons learned, and moving toward best practices. The framework approach emphasizes that the selection of appropriate criteria and indicators is driven by the specific purpose of an analysis. Realistic goals and measures of bioenergy sustainability can be developed systematically with the help of the framework presented here.« less

Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase

PubMed Central

Qiu, Shenfeng; Anderson, Charles T.; Levitt, Pat; Shepherd, Gordon M. G.

2011-01-01

Local hyperconnectivity in the neocortex is a hypothesized pathophysiological state in autism spectrum disorder (ASD). MET, a receptor tyrosine kinase that regulates dendrite and spine morphogenesis, has been established as a risk gene for ASD. Here, we analyzed the synaptic circuit organization of identified pyramidal neurons in the anterior frontal cortex of mice with a dorsal pallium derived, conditional knockout (cKO) of Met. Synaptic mapping by glutamate uncaging identified layer 2/3 as the main source of local excitatory input to layer 5 projection neurons in controls. In both cKO and heterozygotes this pathway was stronger by a factor of ~2. This increase was both sub-layer and projection-class specific, restricted to corticostriatal neurons in upper layer 5B, and not neighboring corticopontine neurons. Paired recordings in cKO slices demonstrated increased unitary connectivity. We propose that excitatory hyperconnectivity in specific neocortical microcircuits constitutes a physiological basis for Met-mediated ASD risk. PMID:21490227

Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase.

PubMed

Qiu, Shenfeng; Anderson, Charles T; Levitt, Pat; Shepherd, Gordon M G

2011-04-13

Local hyperconnectivity in the neocortex is a hypothesized pathophysiological state in autism spectrum disorder (ASD). MET, a receptor tyrosine kinase that regulates dendrite and spine morphogenesis, has been established as a risk gene for ASD. Here, we analyzed the synaptic circuit organization of identified pyramidal neurons in the anterior frontal cortex of mice with a dorsal pallium-derived, conditional knock-out (cKO) of Met. Synaptic mapping by glutamate uncaging identified layer 2/3 as the main source of local excitatory input to layer 5 projection neurons in controls. In both cKO and heterozygotes, this pathway was stronger by a factor of approximately 2. This increase was both sublayer and projection-class specific, restricted to corticostriatal neurons in upper layer 5B and not neighboring corticopontine neurons. Paired recordings in cKO slices demonstrated increased unitary connectivity. We propose that excitatory hyperconnectivity in specific neocortical microcircuits constitutes a physiological basis for Met-mediated ASD risk.

Knockdown of the juvenile hormone receptor gene inhibits soldier-specific morphogenesis in the damp-wood termite Zootermopsis nevadensis (Isoptera: Archotermopsidae).

PubMed

Masuoka, Yudai; Yaguchi, Hajime; Suzuki, Ryutaro; Maekawa, Kiyoto

2015-09-01

The Methoprene-tolerant (Met) protein has been established as a juvenile hormone (JH) receptor. Knockdown of the Met gene caused precocious metamorphosis and suppression of ovarian development. However, the function of Met in caste development of social insects is unclear. In termites, JH acts as a central factor for caste development, especially for soldier differentiation, which involves two molts from workers via a presoldier stage. Increased JH titer in workers is needed for the presoldier molt, and the high JH titer is maintained throughout the presoldier period. Although presoldiers have the fundamental morphological features of soldiers, the nature of the cuticle is completely different from that of soldiers. We expected that JH signals via Met are involved in soldier-specific morphogenesis of the head and mandibles during soldier differentiation, especially in the presoldier period, in natural conditions. To test this hypothesis, we focused on soldier differentiation in an incipient colony of the damp-wood termite Zootermopsis nevadensis. Met homolog (ZnMet) expression in heads increased just after the presoldier molt. This high expression was reduced by ZnMet double stranded (dsRNA) injection before the presoldier molt. Although this treatment did not cause any morphological changes in presoldiers, it caused strong effects on soldiers, their mandibles being significantly shorter and head capsules smaller than those of control soldiers. Injection of ZnMet dsRNA throughout the presoldier stage did not affect the formation of soldier morphology, including cuticle formation. These results suggested that the rapid increase in ZnMet expression and subsequent activation of JH signaling just after the presoldier molt are needed for the formation of soldier-specific weapons. Therefore, besides its established role in insect metamorphosis, the JH receptor signaling also underlies soldier development in termites. Copyright © 2015 Elsevier Ltd. All rights reserved.

A novel potential biomarker for metabolic syndrome in Chinese adults: Circulating protein disulfide isomerase family A, member 4.

PubMed

Chien, Chu-Yen; Hung, Yi-Jen; Shieh, Yi-Shing; Hsieh, Chang-Hsun; Lu, Chieh-Hua; Lin, Fu-Huang; Su, Sheng-Chiang; Lee, Chien-Hsing

2017-01-01

Protein disulfide isomerase (PDI) family members are specific endoplasmic reticulum proteins that are involved in the pathogenesis of numerous diseases including neurodegenerative diseases, cancer and obesity. However, the metabolic effects of PDIA4 remain unclear in humans. The aims of this study were to investigate the associations of serum PDIA4 with the metabolic syndrome (MetS) and its components in Chinese adults. A total of 669 adults (399 men and 270 women) were recruited. Serum PDIA4 concentrations and biochemical variables were recorded. Insulin sensitivity and β-cell function were examined by homeostasis model assessment. MetS was defined based on the modified National Cholesterol Education Program Adult Treatment Panel III criteria for Asia Pacific. The participants with MetS had significantly higher serum PDIA4 levels than those without MetS (P<0.001). After adjustments, the individuals with the highest PDIA4 tertile were associated with a higher risk of MetS than those with the lowest tertile (OR = 4.83, 95% CI: 2.71-8.60). The concentration of PDIA4 showed a stepwise increase with the components of MetS (P<0.001 for trend). The individuals with the highest PDIA4 tertile were significantly associated with waist circumference (OR = 2.41, 95% CI 1.34-4.32), blood pressure (OR = 2.71, 95% CI 1.57-4.67), fasting glucose concentration (OR = 3.17, 95% CI 1.80-5.57), and serum triglycerides (OR = 4.12, 95% CI 2.30-7.37) than those with the lowest tertile. At cutoff point of 15.24 ng/ml, the diagnostic sensitivity and specificity of PDIA4 for the metabolic syndrome were 67 and 72%, respectively, in male patients and 60 and 78%, respectively, in female patients. Finally, the result showed that PDIA4 had a significantly higher area under the curve compared with blood pressure to detect MetS using receiver operating characteristic analysis. Serum PDIA4 concentrations are closely associated to MetS and its components in Chinese adults.

The reliability of the National Cholesterol Education Program's Adult Treatment Panel III (NCEP/ATP III) and the International Diabetes Federation (IDF) definitions in diagnosing metabolic syndrome (MetS) among Gaza Strip Palestinians.

PubMed

Sirdah, Mahmoud M; Abu Ghali, Asmaa S; Al Laham, Nahed A

2012-01-01

Metabolic syndrome (MetS) which is a multifaceted syndrome, has been demonstrated as a common precursor for developing cardiovascular diseases and/or type 2 diabetes mellitus. Different diagnostic definitions for MetS have been proposed and recommended. We set up to evaluate the reliabilities of the National Cholesterol Education Program's Adult Treatment Panel III (NCEP/ATP III) and the International Diabetes Federation (IDF) definitions in diagnosing MetS among Gaza Strip Palestinians. This cross sectional study involved a randomly selected two hundred and thirty apparently healthy adults from the Gaza Strip. Anthropometric measurements, blood pressure, fasting plasma glucose, lipid profile, and questionnaire interviews were performed. The overall prevalence of MetS in our Gaza Strip cohort was 23.0% and 39.5% according to NCEP/ATP III and IDF definitions respectively (p<0.001). No significant differences were seen in the number of MetS components in individuals having MetS by either definition (mean 3.42 ± 0.63 vs 3.52 ± 0.69 respectively, p=0.865). Both IDF and NCEP/ATP III showed an increased prevalence of MetS with age, and body mass index (BMI), however they revealed different prevalence trends with sex. Except for BMI, there were no significant differences in the general and metabolic related characteristics between subjects with MetS of IDF and NCEP/ATP III definitions. Independently of the definition used, MetS is highly prevalent in Gaza Strip population, with a steady increase in MetS prevalence through age and BMI. The IDF definition tends to give higher values for MetS prevalence, and therefore could be more appropriate for diagnosing MetS in Gaza Strip cohort. Copyright © 2012 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Age- and gender-specific population attributable risks of metabolic disorders on all-cause and cardiovascular mortality in Taiwan

PubMed Central

2012-01-01

Background The extent of attributable risks of metabolic syndrome (MetS) and its components on mortality remains unclear, especially with respect to age and gender. We aimed to assess the age- and gender-specific population attributable risks (PARs) for cardiovascular disease (CVD)-related mortality and all-cause mortality for public health planning. Methods A total of 2,092 men and 2,197 women 30 years of age and older, who were included in the 2002 Taiwan Survey of Hypertension, Hyperglycemia, and Hyperlipidemia (TwSHHH), were linked to national death certificates acquired through December 31, 2009. Cox proportional hazard models were used to calculate adjusted hazard ratios and PARs for mortality, with a median follow-up of 7.7 years. Results The respective PAR percentages of MetS for all-cause and CVD-related mortality were 11.6 and 39.2 in men, respectively, and 18.6 and 44.4 in women, respectively. Central obesity had the highest PAR for CVD mortality in women (57.5%), whereas arterial hypertension had the highest PAR in men (57.5%). For all-cause mortality, younger men and post-menopausal women had higher PARs related to Mets and its components; for CVD mortality, post-menopausal women had higher overall PARs than their pre-menopausal counterparts. Conclusions MetS has a limited application to the PAR for all-cause mortality, especially in men; its PAR for CVD mortality is more evident. For CVD mortality, MetS components have higher PARs than MetS itself, especially hypertension in men and waist circumference in post-menopausal women. In addition, PARs for diabetes mellitus and low HDL-cholesterol may exceed 20%. We suggest differential control of risk factors in different subpopulation as a strategy to prevent CVD-related mortality. PMID:22321049

The BDNF Val66Met polymorphism: relation to familiar risk of affective disorder, BDNF levels and salivary cortisol.

PubMed

Vinberg, Maj; Trajkovska, Viktorija; Bennike, Bente; Knorr, Ulla; Knudsen, Gitte M; Kessing, Lars V

2009-10-01

Brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis are considered to play an important role in the pathophysiology of affective disorders. The aim of the present study was to investigate whether the BDNF Val66Met polymorphism is associated with a familiar risk of affective disorder and whether these genotypes affect whole blood BDNF level and salivary cortisol. In a high-risk study, healthy monozygotic and dizygotic twins with and without a co-twin (high- and low-risk twins, respectively) history of affective disorder were identified through nationwide registers. Familiar predisposition to unipolar and bipolar disorder was not associated with any specific genotype pattern of the BDNF Val66Met polymorphism, not in this sample of 124 val/val, 58 val/met and 8 met/met individuals. However, the combination of having a high familiar risk of affective disorder and the met allele was associated with a higher whole blood BDNF (p=0.02) and a higher evening cortisol level (p=0.01), but not with awakening cortisol. Individuals at high risk of affective disorders and who are carriers of the met allele of the Val66Met polymorphism may present with an enhanced stress response. The presence of a specific genotype alone may not enhance the risk of developing an affective episode. Rather, the altered stress response may be expressed only in combination with other risk variants through interactions with the environment.

Immunization with Hypoallergens of shrimp allergen tropomyosin inhibits shrimp tropomyosin specific IgE reactivity.

PubMed

Wai, Christine Y Y; Leung, Nicki Y H; Ho, Marco H K; Gershwin, Laurel J; Shu, Shang An; Leung, Patrick S C; Chu, Ka Hou

2014-01-01

Designer proteins deprived of its IgE-binding reactivity are being sought as a regimen for allergen-specific immunotherapy. Although shrimp tropomyosin (Met e 1) has long been identified as the major shellfish allergen, no immunotherapy is currently available. In this study, we aim at identifying the Met e 1 IgE epitopes for construction of hypoallergens and to determine the IgE inhibitory capacity of the hypoallergens. IgE-binding epitopes were defined by three online computational models, ELISA and dot-blot using sera from shrimp allergy patients. Based on the epitope data, two hypoallergenic derivatives were constructed by site-directed mutagenesis (MEM49) and epitope deletion (MED171). Nine regions on Met e 1 were defined as the major IgE-binding epitopes. Both hypoallergens MEM49 and MED171 showed marked reduction in their in vitro reactivity towards IgE from shrimp allergy patients and Met e 1-sensitized mice, as well as considerable decrease in induction of mast cell degranulation as demonstrated in passive cutaneous anaphylaxis assay. Both hypoallergens were able to induce Met e 1-recognizing IgG antibodies in mice, specifically IgG2a antibodies, that strongly inhibited IgE from shrimp allergy subjects and Met e 1-sensitized mice from binding to Met e 1. These results indicate that the two designer hypoallergenic molecules MEM49 and MED171 exhibit desirable preclinical characteristics, including marked reduction in IgE reactivity and allergenicity, as well as ability to induce blocking IgG antibodies. This approach therefore offers promises for development of immunotherapeutic regimen for shrimp tropomyosin allergy.

Specific Connectivity and Unique Molecular Identity of MET Receptor Tyrosine Kinase Expressing Serotonergic Neurons in the Caudal Dorsal Raphe Nuclei.

PubMed

Kast, Ryan J; Wu, Hsiao-Huei; Williams, Piper; Gaspar, Patricia; Levitt, Pat

2017-05-17

Molecular characterization of neurons across brain regions has revealed new taxonomies for understanding functional diversity even among classically defined neuronal populations. Neuronal diversity has become evident within the brain serotonin (5-HT) system, which is far more complex than previously appreciated. However, until now it has been difficult to define subpopulations of 5-HT neurons based on molecular phenotypes. We demonstrate that the MET receptor tyrosine kinase (MET) is specifically expressed in a subset of 5-HT neurons within the caudal part of the dorsal raphe nuclei (DRC) that is encompassed by the classic B6 serotonin cell group. Mapping from embryonic day 16 through adulthood reveals that MET is expressed almost exclusively in the DRC as a condensed, paired nucleus, with an additional sparse set of MET+ neurons scattered within the median raphe. Retrograde tracing experiments reveal that MET-expressing 5-HT neurons provide substantial serotonergic input to the ventricular/subventricular region that contains forebrain stem cells, but do not innervate the dorsal hippocampus or entorhinal cortex. Conditional anterograde tracing experiments show that 5-HT neurons in the DRC/B6 target additional forebrain structures such as the medial and lateral septum and the ventral hippocampus. Molecular neuroanatomical analysis identifies 14 genes that are enriched in DRC neurons, including 4 neurotransmitter/neuropeptide receptors and 2 potassium channels. These analyses will lead to future studies determining the specific roles that 5-HT MET+ neurons contribute to the broader set of functions regulated by the serotonergic system.

Metal-Catalyzed Oxidation of Protein Methionine Residues in Human Parathyroid Hormone (1-34): Formation of Homocysteine and a Novel Methionine-Dependent Hydrolysis Reaction

PubMed Central

Mozziconacci, Olivier; Ji, Junyan A.; Wang, Y. John; Schöneich, Christian

2013-01-01

The oxidation of PTH(1-34) catalyzed by ferrous ethylenediaminetetraacetic acid (EDTA) is site-specific. The oxidation of PTH(1-34) is localized primarily to the residues Met[8] and His[9]. Beyond the transformation of Met[8] and His[9] into methionine sulfoxide and 2-oxo-histidine, respectively, we observed a hydrolytic cleavage between Met[8] and His[9]. This hydrolysis requires the presence of FeII and oxygen and can be prevented by diethylenetriaminepentaacetic acid (DTPA) and phosphate buffer. Conditions leading to this site-specific hydrolysis also promote the transformation of Met[8] into homocysteine, indicating that the hydrolysis and transformation of homocysteine may proceed through a common intermediate. PMID:23289936

Evaluation of metabolic syndrome prevalence in semi-rural areas of Central Anatolia, Turkey.

PubMed

Arikan, Inci; Metintas, Selma; Kalyoncu, Cemalettin; Colak, Omer; Arikan, Ufuk

2009-08-01

To assess the prevalence and clustering of components of metabolic syndrome (MetS) in semi-rural areas of Central Anatolia, Turkey. This study was conducted between January and August 2008 on a randomly selected sample of participants from semi-rural settlement areas of the Eskisehir province, Central Anatolia, Turkey. The MetS was diagnosed as the presence of 3, or more risk factors according to the National Cholesterol Education Program-Expert Panel Adult Treatment Panel III (NCEP ATP III) criteria. The MetS prevalence was standardized according to age, and logistic regression was used to determine the risk factors affecting prevalence. The study group composed of 2,766 people (40.4% male, 59.6% female). The corrected MetS prevalence according to age was 27.6%, with values of 19.4% in males, and 33.2% in females. The prevalence increased with increasing age in both genders. Groups engaged in heavy physical exercise, and smoking showed decreased odds of having MetS, while MetS risk was lower in men who consumed proper amounts of red meat, fruits, and vegetables. In the MetS group, central obesity risk was higher for women, whereas hypertriglyceridemia risk was higher for men. In the non-MetS group, hypertension, and central obesity risks were higher for women, whereas hypertriglyceridemia risk was higher for men. It was concluded that MetS is a major problem in the Eskisehir province, and it is imperative that changes in lifestyle be made within this population to reduce the risk factors for the condition.

The comorbidity of increased arterial stiffness and microalbuminuria in a survey of middle-aged adults in China.

PubMed

Miao, Rujia; Wu, Liuxin; Ni, Ping; Zeng, Yue; Chen, Zhiheng

2018-05-04

Increased arterial stiffness (iAS) and microalbuminuria (MAU), which may occur simultaneously or separately in the general population and share similar risk factors, are markers of macro- and microvascular injuries. Our research investigated the comorbidity of iAS and MAU in the middle-aged population and examined the heterogeneous effects of metabolic risk factors on iAS and MAU. We selected 11,911 individuals aged 45 to 60 years who underwent a health examination at the 3rd Xiangya Hospital between 2010 and 2014. Metabolic syndrome (MetS) was determined according to IDF/NHLBI/AHA-2009 criteria. Multinomial logistic regression was applied to evaluate the influence of MetS, components of MetS and clusters of MetS on the co-occurrence (MAU(+)/iAS(+)) or non-co-occurrence (MAU(+)/iAS(-) and MAU(-)/iAS(+)) of MAU and iAS. Reference group was MAU(-)/iAS(-). A positive effect of MetS on the presence of MAU(+)/iAS(-), MAU(-)/iAS(+), or MAU(+)/iAS(+) is listed in ascending order based on odds ratios (ORs = 2.11, 2.41, 4.61, respectively; P < 0.05). Compared with MAU(+)/iAS(-), Elevated blood pressure (BP) (OR = 1.62 vs. 4.83, P < 0.05), triglycerides(TG) (OR = 1.20 vs. 1.37, P < 0.05) were more strongly associated with MAU(-)/iAS(+), whereas fasting blood glucose (FBG) was less associated (OR = 1.37 vs. 1.31, P < 0.05). Decreased high-density lipoprotein cholesterol(HDL-c) (OR = 1.84, P < 0.01) and elevated waist circumference(WC) (OR = 1.28 P < 0.01) were the most strongly associated with MAU(+)/iAS(-). Compared with the individuals without MetS, individuals with the elevated BP, FBG, TG and decreased HDL-c cluster had the greatest likelihood of presenting a MAU(-)/iAS(+) (OR = 5.98, P < 0.01) and MAU(+)/iAS(+) (OR = 13.17, P < 0.01), these likelihood was even greater than the cluster with simultaneous alteration in all five MetS components (OR = 3.89 and 10.77, respectively, P < 0.01), which showed the most strongly association with MAU(+)/iAS(+) (OR = 5.22, P < 0.01). Based on the heterogeneous influences of MetS-related risk factors on MAU and iAS, these influences could be selectively targeted to identify different types of vascular injuries.

Development and clinical introduction of automated radiotherapy treatment planning for prostate cancer

NASA Astrophysics Data System (ADS)

Winkel, D.; Bol, G. H.; van Asselen, B.; Hes, J.; Scholten, V.; Kerkmeijer, L. G. W.; Raaymakers, B. W.

2016-12-01

To develop an automated radiotherapy treatment planning and optimization workflow to efficiently create patient specifically optimized clinical grade treatment plans for prostate cancer and to implement it in clinical practice. A two-phased planning and optimization workflow was developed to automatically generate 77Gy 5-field simultaneously integrated boost intensity modulated radiation therapy (SIB-IMRT) plans for prostate cancer treatment. A retrospective planning study (n  =  100) was performed in which automatically and manually generated treatment plans were compared. A clinical pilot (n  =  21) was performed to investigate the usability of our method. Operator time for the planning process was reduced to  <5 min. The retrospective planning study showed that 98 plans met all clinical constraints. Significant improvements were made in the volume receiving 72Gy (V72Gy) for the bladder and rectum and the mean dose of the bladder and the body. A reduced plan variance was observed. During the clinical pilot 20 automatically generated plans met all constraints and 17 plans were selected for treatment. The automated radiotherapy treatment planning and optimization workflow is capable of efficiently generating patient specifically optimized and improved clinical grade plans. It has now been adopted as the current standard workflow in our clinic to generate treatment plans for prostate cancer.

Cost-effectiveness of population-level physical activity interventions: a systematic review.

PubMed

Laine, Johanna; Kuvaja-Köllner, Virpi; Pietilä, Eija; Koivuneva, Mikko; Valtonen, Hannu; Kankaanpää, Eila

2014-01-01

This systematic review synthesizes the evidence on the cost-effectiveness of population-level interventions to promote physical activity. A systematic literature search was conducted between May and August 2013 in four databases: PubMed, Scopus, Web of Science, and SPORTDiscus. Only primary and preventive interventions aimed at promoting and maintaining physical activity in wide population groups were included. An economic evaluation of both effectiveness and cost was required. Secondary interventions and interventions targeting selected population groups or focusing on single individuals were excluded. Interventions were searched for in six different categories: (1) environment, (2) built environment, (3) sports clubs and enhanced access, (4) schools, (5) mass media and community-based, and (6) workplace. The systematic search yielded 2058 articles, of which 10 articles met the selection criteria. The costs of interventions were converted to costs per person per day in 2012 U.S. dollars. The physical activity results were calculated as metabolic equivalent of task hours (MET-hours, or MET-h) gained per person per day. Cost-effectiveness ratios were presented as dollars per MET-hours gained. The intervention scale and the budget impact of interventions were taken into account. The most efficient interventions to increase physical activity were community rail-trails ($.006/MET-h), pedometers ($.014/MET-h), and school health education programs ($.056/MET-h). Improving opportunities for walking and biking seems to increase physical activity cost-effectively. However, it is necessary to be careful in generalizing the results because of the small number of studies. This review provides important information for decision makers.

Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 1.

PubMed

Cheruvallath, Zacharia; Tang, Mingnam; McBride, Christopher; Komandla, Mallareddy; Miura, Joanne; Ton-Nu, Thu; Erikson, Phil; Feng, Jun; Farrell, Pamela; Lawson, J David; Vanderpool, Darin; Wu, Yiqin; Dougan, Douglas R; Plonowski, Artur; Holub, Corine; Larson, Chris

2016-06-15

Methionine aminopeptidase 2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. Pre-clinical and clinical studies suggest that MetAP2 inhibitors could be used as a novel treatment for obesity. Herein we describe our use of fragment screening methods and structural biology to quickly identify and elaborate an indazole fragment into a series of reversible MetAP2 inhibitors with <10nM potency, excellent selectivity, and favorable in vitro safety profiles. Copyright © 2016 Elsevier Ltd. All rights reserved.

Expressed information needs of patients with osteoporosis and/or fragility fractures: a systematic review.

PubMed

Raybould, Grace; Babatunde, Opeyemi; Evans, Amy L; Jordan, Joanne L; Paskins, Zoe

2018-05-08

This systematic review identified patients have unmet information needs about the nature of osteoporosis, medication, self-management and follow-up. Clinician knowledge and attitudes appear to be of key importance in determining whether these needs are met. Unmet information needs appear to have psychosocial consequences and result in poor treatment adherence. Patient education is an integral component of the management of osteoporosis, yet patients are dissatisfied with the information they receive and see this as an area of research priority. This study aimed to describe and summarise the specific expressed information needs of patients in previously published qualitative research. Using terms relating to osteoporosis, fragility fracture and information needs, seven databases were searched. Articles were screened using predefined inclusion and exclusion criteria. Full-text articles selected for inclusion underwent data extraction and quality appraisal. Findings were drawn together using narrative synthesis. The search identified 11,024 articles. Sixteen empirical studies were included in the review. Thematic analysis revealed three overarching themes relating to specific information needs, factors influencing whether information needs are met and the impact of unmet information needs. Specific information needs identified included the following: the nature of osteoporosis/fracture risk; medication; self-management and understanding the role of dual energy x-ray absorptiometry and follow-up. Perceived physician knowledge and attitudes, and the attitudes, beliefs and behaviours of patients were important factors in influencing whether information needs were met, in addition to contextual factors and the format of educational resources. Failure to elicit and address information needs appears to be associated with poor treatment adherence, deterioration of the doctor-patient relationship and important psychosocial consequences. This is the first study to describe the information needs of patients with osteoporosis and fracture, the impact of this information gap and possible solutions. Further research is needed to co-design and evaluate educational interventions with patients.

Identification of both NK1 and NK2 receptors in guinea-pig airways.

PubMed Central

McKee, K. T.; Millar, L.; Rodger, I. W.; Metters, K. M.

1993-01-01

1. NK1 and NK2 receptors have been characterized in guinea-pig lung membrane preparations by use of [125I-Tyr8]-substance P and [125I]-neurokinin A binding assays in conjunction with tachykinin-receptor selective agonists ([Sar9Met(O2)11]substance P for NK1 and [beta Ala8]neurokinin A (4-10) for NK2) and antagonists (CP-99,994 for NK1 and SR48968 for NK2). 2. The presence of high affinity, G-protein-coupled NK1 receptors in guinea-pig lung parenchymal membranes has been confirmed. The rank order of affinity for competing tachykinins was as predicted for an NK1 receptor: substance P = [Sar9Met(O2)11]substance P > substance P-methyl ester = physalaemin > neurokinin A = neurokinin B >> [beta Ala8]neurokinin A (4-10). The novel NK1 antagonist CP-99,994 has a Ki of 0.4 nM at this NK1 site. 3. In order to characterize [125I]-neurokinin A binding to guinea-pig lung, the number of [125I]-neurokinin A specific binding sites was increased 3-4 fold by purification of the parenchymal membranes over discontinuous sucrose gradients. The rank order of affinity determined for NK1- and NK2-receptor agonists and antagonists in competition for these sites showed that the majority (80%) of [125I]-neurokinin A specific binding was also to the NK1 receptor. 4. Under conditions where the guinea-pig lung parenchymal NK1 receptor was fully occupied by a saturating concentration of either [Sar9Met(O2)11]substance P (1 microM) or CP-99,994 (2.7 microM), residual [125I]-neurokinin A specific binding was inhibited in a concentration-dependent manner by both [beta Ala8]neurokinin A and SR48968. This result shows that the NK2 receptor is also present in these preparations.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7694756

Molecular dynamics guided development of indole based dual inhibitors of EGFR (T790M) and c-MET.

PubMed

Singh, Pankaj Kumar; Silakari, Om

2018-04-25

Secondary acquired mutation in EGFR, i.e. EGFR T790M and amplification of c-MET form the two key components of resistant NSCLC. Thus, previously published pharmacophore models of EGFR T790M and c-MET were utilized to screen an in-house database. On the basis of fitness score, indole-pyrimidine scaffold was selected for further evaluation. Derivatives of indole-pyrimidine scaffold with variedly substituted aryl substitutions were sketched and then docked in both the targets. These docked complexes were then subjected to molecular dynamic simulations, to study the stability of the complexes and evaluate orientations of the designed molecules in the catalytic domain of the selected kinases. Afterwards, the complexes were subjected to MM-GBSA calculation, to study the effect of substitutions on binding affinity of double mutant EGFR towards these small molecules. Finally, the designed molecules were synthesized and evaluated for their inhibitory potential against both the kinases using in vitro experiments. Additionally, the compounds were also evaluated against EGFR (L858R) to determine their selectivity towards double mutant, resistant kinase [EGFR (T790M)]. Compound 7a and 7c were found to be possess nanomolar range inhibitory (IC 50 ) potential against EGFR (T790M), 7 h showed good inhibitory potential against c-MET with IC 50 value of 0.101 µM. Overall, this work is one of the earliest report of compounds having significant dual inhibitory potential against secondary acquired EGFR and cMET, with IC 50 values in nanomolar range. Copyright © 2018 Elsevier Inc. All rights reserved.

Western dietary pattern interaction with APOC3 polymorphism in the risk of metabolic syndrome: Tehran Lipid and Glucose Study.

PubMed

Hosseini-Esfahani, Firoozeh; Mirmiran, Parvin; Daneshpour, Maryam S; Mehrabi, Yadollah; Hedayati, Mehdi; Zarkesh, Maryam; Azizi, Fereidoun

2014-01-01

Gene-dietary pattern interactions may contribute to the determination of a susceptibility to metabolic syndrome (MetS). The aim of this study was to evaluate the potential interactions of dietary patterns with the common genetic variant of APOC3 in relation to MetS in adults. In this individual matched nested case-control study, 755 MetS subjects and 755 controls were selected from among participants in the Tehran Lipid and Glucose Study. Dietary patterns were determined by factor analysis. APOC3 3238C>G rs5128 was genotyped by polymerase chain reaction and restriction fragment length polymorphism. Fat-sweet, healthy and Western dietary patterns (WDP) were extracted from the data. In the joint analysis, the associations of the WDP and APOC3 rs5128 with MetS risk tended to be dependent on APOC3 3238C>G gene variants (p for interaction = 0.009) in women. The MetS risk was increased in women with the CC genotype with increasing tertiles of WDP scores compared with women with the CG + GG genotype, whose MetS risk was decreased with increasing tertiles of WDP scores. In addition, we found that intakes of fast food, salty snacks and soft drinks showed significant interactions with the rs5128 genotypes in relation to MetS risk (p for interactions <0.05). The results obtained demonstrate a diet-gene interaction between APOC3 rs5128 polymorphism and the WDP in relation to MetS risk. © 2014 S. Karger AG, Basel.

Physical dose of therapeutic exercises in institutional neck rehabilitation.

PubMed

Wasenius, Niko; Karapalo, Teppo; Sjögren, Tuulikki; Pekkonen, Mika; Mälkiä, Esko

2013-03-01

To determine the intensity and volume of therapeutic exercises during a standard 13-day inpatient neck rehabilitation course in relation to overall physical activity in rehabilitation and everyday life. Cross-sectional study. Subjects (n = 19; 16 women and 3 men; mean age 48.6 years, standard deviation (SD) 6.6) with chronic non-specific neck pain were recruited from two inpatient neck rehabilitation courses. Intensity and volume of therapeutic exercises and physical activity were measured in metabolic equivalents (METs) with an objective measurement device and all-time recall questionnaire. Maximum oxygen uptake was determined in METs (METc) by direct maximal cycle ergometer. Subjects' mean METc was 7.2 METs (SD 1.4) or 25.3 ml/kg/min (SD 4.8). Intensity of all therapeutic exercises was 1.9 METs or 27 %METc (SD 5.1) and volume 7.7 MET-hours/week. Intensity of specific neck and shoulder exercises was 2.0 METs or 28 %METc (SD 5.4) and volume 2.5 MET-hours/week. In addition, subjects were more active in everyday life than in inpatient rehabilitation. The therapeutic exercise dose failed to reach previously reported target values for pain relief. The dose of therapeutic exercises and confounding physical activity should be carefully controlled in pain rehabilitation programmes.

Relationship between Metabolic Syndrome and Its Components with Psychological Distress.

PubMed

Roohafza, Hamidreza; Sadeghi, Masoumeh; Naghnaeian, Mina; Shokouh, Pedram; Ahmadi, Abdollah; Sarrafzadegan, Nizal

2014-01-01

Background. Metabolic syndrome (MetS) and psychological distress are hypothesized to have a bidirectional relationship. According to their high prevalence in most populations, appraisal of this theory would be of great clinical and research interest. Methods. Data were available as part of the Isfahan Healthy Heart Program (IHHP). A total of 9553 men and women aged ≥19 years from three counties in central Iran were selected. Measurements consisted of serologic tests, anthropometrics, and self-reported 12-item general health questionnaire. Logistic regression analysis was used to find the association between MetS, MetS components, and distress level. Results. The mean age of 9553 participants (50% male) was 38.7 ± 15.8 years. After adjusting for demographic factors, MetS (OR = 1.25, 95% CI: 1.01-1.37), central obesity (OR = 1.40, 95% CI: 1.15-1.49), and hypertension (OR = 1.55, 95% CI: 1.42-1.70) were associated with high distress level. However, after adding smoking status and low-density lipoprotein cholesterol to the adjustment factors, hypertension (OR = 1.79, 95% CI: 1.53-1.98) and central obesity (OR = 1.41, 95% CI: 1.17-1.55), but not the MetS, remained significantly associated with distress level. Conclusion. The presence of association between the MetS as well as its key components and high distress level signifies the importance of integrating psychological assessment and intervention in the standard management of MetS patients.

Alterations in triglyceride rich lipoproteins are related to endothelial dysfunction in metabolic syndrome.

PubMed

Lucero, Diego; López, Graciela I; Gorzalczany, Susana; Duarte, Mariano; González Ballerga, Esteban; Sordá, Juan; Schreier, Laura; Zago, Valeria

2016-08-01

Our aim was to analyze the effect of circulating triglyceride rich lipoprotein (TRL) on endothelial function in metabolic syndrome (MetS). We studied 40 patients with MetS (ATPIII), divided into those presenting normal endothelial function (n=19) and those with endothelial dysfunction (n=21) by means of the evaluation of pulse wave velocity, before and after brachial artery ischemia. In fasting serum we measured lipid and lipoprotein profile, insulin and glucose (HOMA-IR). Moreover, isolated TRL (d<1006g/l) were chemically characterized. In parallel, using randomly selected TRL from MetS patients with endothelial dysfunction (n=6) and MetS patients with normal endothelial function (n=6), the ability of TRL to inhibit ACh-induced vasorelaxation (10(-9)-10(-5)mM) on aortic rings previously pre-contracted by noradrenaline (10(-8)mM) was evaluated. Interestingly, TRL isolated from MetS patients presenting endothelial dysfunction showed triglyceride over-enrichment (59.1±4.8 vs. 54.1±4.7%; p=0.04), even after adjusting by potential confounders (p=0.05). In addition, while TRL resulting from both MetS groups significantly inhibited endothelium dependent vasorelaxation (p<0.001), TRL from MetS patients with endothelial dysfunction showed a strong tendency to a greater inhibition of vasorelaxation (p=0.06). Moreover, TRL-triglyceride (%) showed a strong tendency to correlate with the grade of vasorelaxation inhibition exerted by TRL (r=0.60; p=0.05). These results, taken together, would allow inferring for the first time that the predominance of triglyceride over-enriched TRL in circulation in MetS would induce endothelial dysfunction, contributing to the inherent cardiovascular risk of MetS. Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Compact Ceramic Microchannel Heat Exchangers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lewinsohn, Charles

The objective of the proposed work was to demonstrate the feasibility of a step change in power plant efficiency at a commercially viable cost, by obtaining performance data for prototype, compact, ceramic microchannel heat exchangers. By performing the tasks described in the initial proposal, all of the milestones were met. The work performed will advance the technology from Technology Readiness Level 3 (TRL 3) to Technology Readiness Level 4 (TRL 4) and validate the potential of using these heat exchangers for enabling high efficiency solid oxide fuel cell (SOFC) or high-temperature turbine-based power plants. The attached report will describe howmore » this objective was met. In collaboration with The Colorado School of Mines (CSM), specifications were developed for a high temperature heat exchanger for three commercial microturbines. Microturbines were selected because they are a more mature commercial technology than SOFC, they are a low-volume and high-value target for market entry of high-temperature heat exchangers, and they are essentially scaled-down versions of turbines used in utility-scale power plants. Using these specifications, microchannel dimensions were selected to meet the performance requirements. Ceramic plates were fabricated with microchannels of these dimensions. The plates were tested at room temperature and elevated temperature. Plates were joined together to make modular, heat exchanger stacks that were tested at a variety of temperatures and flow rates. Although gas flow rates equivalent to those in microturbines could not be achieved in the laboratory environment, the results showed expected efficiencies, robust operation under significant temperature gradients at high temperature, and the ability to cycle the stacks. Details of the methods and results are presented in this final report.« less

Inhibition of Mycobacterium tuberculosis Methionine Aminopeptidases by Bengamide Derivatives

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lu, Jing-Ping; Yuan, Xiu-Hua; Yuan, Hai

Methionine aminopeptidase (MetAP) carries out an essential function of protein N-terminal processing in many bacteria and is a promising target for the development of novel antitubercular agents. Natural bengamides potently inhibit the proliferation of mammalian cells by targeting MetAP enzymes, and the X-ray crystal structure of human type 2 MetAP in complex with a bengamide derivative reveals the key interactions at the active site. By preserving the interactions with the conserved residues inside the binding pocket while exploring the differences between bacterial and human MetAPs around the binding pocket, seven bengamide derivatives were synthesized and evaluated for inhibition of MtMetAP1amore » and MtMetAP1c in different metalloforms, inhibition of M. tuberculosis growth in replicating and non-replicating states, and inhibition of human K562 cell growth. Potent inhibition of MtMetAP1a and MtMetAP1c and modest growth inhibition of M. tuberculosis were observed for some of these derivatives. Crystal structures of MtMetAP1c in complex with two of the derivatives provided valuable structural information for improvement of these inhibitors for potency and selectivity.« less

Use of medical expulsive therapy in children: An assessment of nationwide practice patterns and outcomes

PubMed Central

Ellison, Jonathan S.; Merguerian, Paul A.; Fu, Benjamin C.; Holt, Sarah K.; Lendvay, Thomas S.; Gore, John L.; Shnorhavorian, Margarett

2018-01-01

Summary Introduction Early data support the use of medical expulsive therapy (MET) in children. However, little is known regarding use or outcomes associated with MET outside of pediatric-specific practices. Using a national administrative dataset, we sought to characterize utilization patterns of MET as well as assess outcomes associated with MET exposure. Study design We interrogated the MarketScan Commercial Claims and Encounters database to identify children under the age of 18 presenting to the emergency department (ED) with any diagnosis of upper urinary tract calculi (UUTC, including renal and ureteral calculi). MET exposure was defined as having a prescription filled for a MET agent within 1 week of the ED encounter. Characteristics of children receiving MET were defined and outcomes compared between children with and without MET exposure. Results Of 1325 children included in the study, 13.2% received MET, including 15.4% of children with a diagnosis of “calculus of the ureter.” MET use increased significantly throughout the study period (p = 0.004), although only 30.4% of children considered potential MET candidates received MET in the final year of the study (2013). Among all patients, receipt of MET was associated with male gender, presence of comorbidity, provider-type (urologist), and year of diagnosis, although among those with a specific diagnosis of “calculus of the ureter,” only year of diagnosis remained a significant factor. Rates of unplanned physician visits and surgical interventions were similar between groups. Children receiving MET were more likely to receive follow-up imaging, although only 46% of children with ureteral calculi had appropriate follow-up imaging within 90 days, regardless of MET exposure. Odds ratios of factors and outcomes associated with MET exposure are shown in the Table. Discussion Although early data support safety and efficacy MET in children, nationwide use in children is low among potential candidates for MET. For children with ureteral calculi, only year of diagnosis was a significant factor associated with MET use. No difference in unplanned physician visits or surgical interventions was noted. Most notable, however, was the low rate of follow-up imaging within 90 days for children presenting acutely with UUTC. Conclusions Use of MET for children with ureteral calculi is increasing, although still fewer than a third of children considered potential candidates receive this treatment. Follow-up imaging is not obtained for many children with ureteral calculi. Future work is needed to standardize management and follow-up protocols for children with acute renal colic. PMID:28483465

Half-Unit Insulin Pens: Disease Management in Patients With Diabetes Who Are Sensitive to Insulin.

PubMed

Klonoff, David C; Nayberg, Irina; Stauder, Udo; Oualali, Hamid; Domenger, Catherine

2017-05-01

Insulin pens represent a significant technological advancement in diabetes management. While the vast majority have been designed with 1U-dosing increments, improved accuracy and precision facilitated by half-unit increments may be particularly significant in specific patients who are sensitive to insulin. These include patients with low insulin requirements and in those requiring more precise dose adjustments, such as the pediatric patient population. This review summarized functional characteristics of insulin half-unit pens (HUPs) and their effect on user experience. The literature search was restricted to articles published in English between January 1, 2000, and January 1, 2015. A total of 17 publications met the set criteria and were included in the review. Overall, studies outlined characteristics for 4 insulin HUPs. Based on their functionality, the pens were generally similar and all met the ISO 11608-1 criteria for accuracy. However, some had specific advantageous features in terms of size, weight, design, dialing torque, and injection force. Although limited, the currently available user preference studies in children and adolescents with diabetes and their carers suggest that the selection of an HUP is likely to be influenced by a combination of factors such as these, in addition to the prescribed insulin and dosing regimen. Insulin HUPs are likely to be a key diabetes management tool for patients who are sensitive to insulin; specific pen features may further advance diabetes management in these populations.

pH-regulated metal-ligand switching in the HM loop of ATP7A: a new paradigm for metal transfer chemistry.

PubMed

Kline, Chelsey D; Gambill, Benjamin F; Mayfield, Mary; Lutsenko, Svetlana; Blackburn, Ninian J

2016-08-01

Cuproproteins such as PHM and DBM mature in late endosomal vesicles of the mammalian secretory pathway where changes in vesicle pH are employed for sorting and post-translational processing. Colocation with the P1B-type ATPase ATP7A suggests that the latter is the source of copper and supports a mechanism where selectivity in metal transfer is achieved by spatial colocation of partner proteins in their specific organelles or vesicles. In previous work we have suggested that a lumenal loop sequence located between trans-membrane helices TM1 and TM2 of the ATPase, and containing five histidines and four methionines, acts as an organelle-specific chaperone for metallation of the cuproproteins. The hypothesis posits that the pH of the vesicle regulates copper ligation and loop conformation via a mechanism which involves His to Met ligand switching induced by histidine protonation. Here we report the effect of pH on the HM loop copper coordination using X-ray absorption spectroscopy (XAS), and show via selenium substitution of the Met residues that the HM loop undergoes similar conformational switching to that found earlier for its partner PHM. We hypothesize that in the absence of specific chaperones, HM motifs provide a template for building a flexible, pH-sensitive transfer site whose structure and function can be regulated to accommodate the different active site structural elements and pH environments of its partner proteins.

Identification of an Interaction between VWF rs7965413 and Platelet Count as a Novel Risk Marker for Metabolic Syndrome: An Extensive Search of Candidate Polymorphisms in a Case-Control Study

PubMed Central

Nakatochi, Masahiro; Ushida, Yasunori; Yasuda, Yoshinari; Yoshida, Yasuko; Kawai, Shun; Kato, Ryuji; Nakashima, Toru; Iwata, Masamitsu; Kuwatsuka, Yachiyo; Ando, Masahiko; Hamajima, Nobuyuki; Kondo, Takaaki; Oda, Hiroaki; Hayashi, Mutsuharu; Kato, Sawako; Yamaguchi, Makoto; Maruyama, Shoichi; Matsuo, Seiichi; Honda, Hiroyuki

2015-01-01

Although many single nucleotide polymorphisms (SNPs) have been identified to be associated with metabolic syndrome (MetS), there was only a slight improvement in the ability to predict future MetS by the simply addition of SNPs to clinical risk markers. To improve the ability to predict future MetS, combinational effects, such as SNP—SNP interaction, SNP—environment interaction, and SNP—clinical parameter (SNP × CP) interaction should be also considered. We performed a case-control study to explore novel SNP × CP interactions as risk markers for MetS based on health check-up data of Japanese male employees. We selected 99 SNPs that were previously reported to be associated with MetS and components of MetS; subsequently, we genotyped these SNPs from 360 cases and 1983 control subjects. First, we performed logistic regression analyses to assess the association of each SNP with MetS. Of these SNPs, five SNPs were significantly associated with MetS (P < 0.05): LRP2 rs2544390, rs1800592 between UCP1 and TBC1D9, APOA5 rs662799, VWF rs7965413, and rs1411766 between MYO16 and IRS2. Furthermore, we performed multiple logistic regression analyses, including an SNP term, a CP term, and an SNP × CP interaction term for each CP and SNP that was significantly associated with MetS. We identified a novel SNP × CP interaction between rs7965413 and platelet count that was significantly associated with MetS [SNP term: odds ratio (OR) = 0.78, P = 0.004; SNP × CP interaction term: OR = 1.33, P = 0.001]. This association of the SNP × CP interaction with MetS remained nominally significant in multiple logistic regression analysis after adjustment for either the number of MetS components or MetS components excluding obesity. Our results reveal new insight into platelet count as a risk marker for MetS. PMID:25646961

Identification of an interaction between VWF rs7965413 and platelet count as a novel risk marker for metabolic syndrome: an extensive search of candidate polymorphisms in a case-control study.

PubMed

Nakatochi, Masahiro; Ushida, Yasunori; Yasuda, Yoshinari; Yoshida, Yasuko; Kawai, Shun; Kato, Ryuji; Nakashima, Toru; Iwata, Masamitsu; Kuwatsuka, Yachiyo; Ando, Masahiko; Hamajima, Nobuyuki; Kondo, Takaaki; Oda, Hiroaki; Hayashi, Mutsuharu; Kato, Sawako; Yamaguchi, Makoto; Maruyama, Shoichi; Matsuo, Seiichi; Honda, Hiroyuki

2015-01-01

Although many single nucleotide polymorphisms (SNPs) have been identified to be associated with metabolic syndrome (MetS), there was only a slight improvement in the ability to predict future MetS by the simply addition of SNPs to clinical risk markers. To improve the ability to predict future MetS, combinational effects, such as SNP-SNP interaction, SNP-environment interaction, and SNP-clinical parameter (SNP × CP) interaction should be also considered. We performed a case-control study to explore novel SNP × CP interactions as risk markers for MetS based on health check-up data of Japanese male employees. We selected 99 SNPs that were previously reported to be associated with MetS and components of MetS; subsequently, we genotyped these SNPs from 360 cases and 1983 control subjects. First, we performed logistic regression analyses to assess the association of each SNP with MetS. Of these SNPs, five SNPs were significantly associated with MetS (P < 0.05): LRP2 rs2544390, rs1800592 between UCP1 and TBC1D9, APOA5 rs662799, VWF rs7965413, and rs1411766 between MYO16 and IRS2. Furthermore, we performed multiple logistic regression analyses, including an SNP term, a CP term, and an SNP × CP interaction term for each CP and SNP that was significantly associated with MetS. We identified a novel SNP × CP interaction between rs7965413 and platelet count that was significantly associated with MetS [SNP term: odds ratio (OR) = 0.78, P = 0.004; SNP × CP interaction term: OR = 1.33, P = 0.001]. This association of the SNP × CP interaction with MetS remained nominally significant in multiple logistic regression analysis after adjustment for either the number of MetS components or MetS components excluding obesity. Our results reveal new insight into platelet count as a risk marker for MetS.

Adult Attachment Interview Discourse Patterns Predict Metabolic Syndrome in Midlife

PubMed Central

Davis, Cynthia R.; Usher, Nicole; Dearing, Eric; Barkai, Ayelet R.; Crowell-Doom, Cindy; Mantzoros, Christos S.; Crowell, Judith A.

2017-01-01

Objective Adult attachment discourse patterns and current family relationship quality were examined as predictors of health behaviors and number of Metabolic Syndrome (MetS) criteria met. Methods A sample of 215 White/European American and Black/African American adults, aged 35 to 55, were examined cross-sectionally. Discourse was assessed with the Adult Attachment Interview (AAI), specifically: 1) coherence, a marker of attachment security, 2) unresolved trauma/loss, a marker of disorganized and distorted cognition related to trauma, and 3) idealization, the tendency to minimize the impact of stressful experiences. Health behaviors of diet, exercise, smoking and alcohol use were also assessed, as were adverse childhood experiences, current depressive symptoms and relationship functioning. MetS includes hypertension, hyperglycemia, high triglycerides, low HDL cholesterol, and obesity. Results Using path analysis and accounting for childhood adversity and depressive symptoms, AAI coherence and unresolved trauma or loss were directly linked to number of MetS criteria met (β = −.22 and .21 respectively). Idealization was indirectly linked to MetS through poor diet (β = −.26 and −.36 respectively), predicting 21% of the variance in number of MetS criteria met. Conclusions Attachment representations related to stress appraisal and care-seeking behaviors appear to serve as cognitive mechanisms increasing risk of MetS. PMID:25264975

Distinct projection targets define subpopulations of mouse brainstem vagal neurons that express the autism-associated MET receptor tyrosine kinase.

PubMed

Kamitakahara, Anna; Wu, Hsiao-Huei; Levitt, Pat

2017-12-15

Detailed anatomical tracing and mapping of the viscerotopic organization of the vagal motor nuclei has provided insight into autonomic function in health and disease. To further define specific cellular identities, we paired information based on visceral connectivity with a cell-type specific marker of a subpopulation of neurons in the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguus (nAmb) that express the autism-associated MET receptor tyrosine kinase. As gastrointestinal disturbances are common in children with autism spectrum disorder (ASD), we sought to define the relationship between MET-expressing (MET+) neurons in the DMV and nAmb, and the gastrointestinal tract. Using wholemount tissue staining and clearing, or retrograde tracing in a MET EGFP transgenic mouse, we identify three novel subpopulations of EGFP+ vagal brainstem neurons: (a) EGFP+ neurons in the nAmb projecting to the esophagus or laryngeal muscles, (b) EGFP+ neurons in the medial DMV projecting to the stomach, and (b) EGFP+ neurons in the lateral DMV projecting to the cecum and/or proximal colon. Expression of the MET ligand, hepatocyte growth factor (HGF), by tissues innervated by vagal motor neurons during fetal development reveal potential sites of HGF-MET interaction. Furthermore, similar cellular expression patterns of MET in the brainstem of both the mouse and nonhuman primate suggests that MET expression at these sites is evolutionarily conserved. Together, the data suggest that MET+ neurons in the brainstem vagal motor nuclei are anatomically positioned to regulate distinct portions of the gastrointestinal tract, with implications for the pathophysiology of gastrointestinal comorbidities of ASD. © 2017 Wiley Periodicals, Inc.

Targeted deletion of c-Met in thymic epithelial cells leads to an autoimmune phenotype

PubMed Central

Su, Min; Hu, Rong; Song, Yinhong; Liu, Yalan; Lai, Laijun

2017-01-01

Hepatocyte growth factor (HGF) and its receptor c-Met signaling have been implicated in regulating various types of cells including epithelial cells. We have previously reported that c-Met is expressed by thymic epithelial cells (TECs), and that in vivo administration of hybrid cytokines containing IL-7 and the beta- or alpha-chain of HGF significantly increase the number of TECs. In order to study the role of c-Met signaling in TECs, we generated conditional knockout (cKO) mice in which c-Met was specifically deleted in TECs using a Foxn1-Cre transgene. We show here that c-Met deficiency in TECs results in age-progressive reduction in TEC number and reduced number of regulatory T cells. Consequently, c-Met TEC cKO mice displayed an autoimmune phenotype. Thus, c-Met signaling in TECs is important for the maintenance of TECs and immune self-tolerance. PMID:29363160

Coalition Factor in the Evolution of Non-Kin Altruism

NASA Astrophysics Data System (ADS)

Dessalles, Jean-Louis

Animal behavior is often altruistic. In the frame of the theory of natural selection, altruism can only exist under specific conditions like kin selection or reciprocal cooperation. We show that reciprocal cooperation, which is generally invoked to explain non-kin altruism, requires very restrictive conditions to be stable. Some of these conditions are not met in many cases of altruism observed in nature. In search of another explanation of non-kin altruism, we consider Zahavis's theory of prestige. We extend it to propose a "political" model of altruism. We give evidence showing that non-kin altruism can evolve in the context of inter-subgroup competition. Under such circumstances, altruistic behavior can be used by individuals to advertise their quality as efficient coalition members. In this model, only abilities which positively correlate with the subgroup success can evolve into altruistic behaviors.

Variant BDNF-Val66Met Polymorphism is Associated with Layer-Specific Alterations in GABAergic Innervation of Pyramidal Neurons, Elevated Anxiety and Reduced Vulnerability of Adolescent Male Mice to Activity-Based Anorexia.

PubMed

Chen, Yi-Wen; Surgent, Olivia; Rana, Barkha S; Lee, Francis; Aoki, Chiye

2017-08-01

Previously, we determined that rodents' vulnerability to food restriction (FR)-evoked wheel running during adolescence (activity-based anorexia, ABA) is associated with failures to increase GABAergic innervation of hippocampal and medial prefrontal pyramidal neurons. Since brain-derived neurotrophic factor (BDNF) promotes GABAergic synaptogenesis, we hypothesized that individual differences in this vulnerability may arise from differences in the link between BDNF bioavailability and FR-evoked wheel running. We tested this hypothesis in male BDNF-Val66Met knock-in mice (BDNFMet/Met), known for reduction in the activity-dependent BDNF secretion and elevated anxiety-like behaviors. We found that 1) in the absence of FR or a wheel (i.e., control), BDNFMet/Met mice are more anxious than wild-type (WT) littermates, 2) electron microscopically verified GABAergic innervations of pyramidal neurons of BDNFMet/Met mice are reduced at distal dendrites in hippocampal CA1 and medial prefrontal cortex, 3) following ABA, WT mice exhibit anxiety equal to those of the BDNFMet/Met mice and have lost GABAergic innervation along distal dendrites, 4) BDNFMet/Met mice show blunted ABA vulnerability, and 5) unexpectedly, GABAergic innervation is higher at somata of BDNFMet/Met mice than of WT. We conclude that lamina-specific GABAergic inhibition is important for regulating anxiety, whether arising from environmental stress, such as food deprivation, or genetically, such as BDNFMet/Met single nucleotide polymorphism. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Effect of essential amino acids on enteroids: Methionine deprivation suppresses proliferation and affects differentiation in enteroid stem cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saito, Yuki; Iwatsuki, Ken; Hanyu, Hikaru

We investigated the effects of essential amino acids on intestinal stem cell proliferation and differentiation using murine small intestinal organoids (enteroids) from the jejunum. By selectively removing individual essential amino acids from culture medium, we found that 24 h of methionine (Met) deprivation markedly suppressed cell proliferation in enteroids. This effect was rescued when enteroids cultured in Met deprivation media for 12 h were transferred to complete medium, suggesting that Met plays an important role in enteroid cell proliferation. In addition, mRNA levels of the stem cell marker leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) decreased in enteroids grown in Met deprivationmore » conditions. Consistent with this observation, Met deprivation also attenuated Lgr5-EGFP fluorescence intensity in enteroids. In contrast, Met deprivation enhanced mRNA levels of the enteroendocrine cell marker chromogranin A (ChgA) and markers of K cells, enterochromaffin cells, goblet cells, and Paneth cells. Immunofluorescence experiments demonstrated that Met deprivation led to an increase in the number of ChgA-positive cells. These results suggest that Met deprivation suppresses stem cell proliferation, thereby promoting differentiation. In conclusion, Met is an important nutrient in the maintenance of intestinal stem cells and Met deprivation potentially affects cell differentiation. - Highlights: • Met influences the proliferation of enteroids. • Met plays a crucial role in the maintenance of stem cells. • Met deprivation potentially promotes differentiation into secretory cells.« less

Immunization with Hypoallergens of Shrimp Allergen Tropomyosin Inhibits Shrimp Tropomyosin Specific IgE Reactivity

PubMed Central

Wai, Christine Y. Y.; Leung, Nicki Y. H.; Ho, Marco H. K.; Gershwin, Laurel J.; Shu, Shang An; Leung, Patrick S. C.; Chu, Ka Hou

2014-01-01

Designer proteins deprived of its IgE-binding reactivity are being sought as a regimen for allergen-specific immunotherapy. Although shrimp tropomyosin (Met e 1) has long been identified as the major shellfish allergen, no immunotherapy is currently available. In this study, we aim at identifying the Met e 1 IgE epitopes for construction of hypoallergens and to determine the IgE inhibitory capacity of the hypoallergens. IgE-binding epitopes were defined by three online computational models, ELISA and dot-blot using sera from shrimp allergy patients. Based on the epitope data, two hypoallergenic derivatives were constructed by site-directed mutagenesis (MEM49) and epitope deletion (MED171). Nine regions on Met e 1 were defined as the major IgE-binding epitopes. Both hypoallergens MEM49 and MED171 showed marked reduction in their in vitro reactivity towards IgE from shrimp allergy patients and Met e 1-sensitized mice, as well as considerable decrease in induction of mast cell degranulation as demonstrated in passive cutaneous anaphylaxis assay. Both hypoallergens were able to induce Met e 1-recognizing IgG antibodies in mice, specifically IgG2a antibodies, that strongly inhibited IgE from shrimp allergy subjects and Met e 1-sensitized mice from binding to Met e 1. These results indicate that the two designer hypoallergenic molecules MEM49 and MED171 exhibit desirable preclinical characteristics, including marked reduction in IgE reactivity and allergenicity, as well as ability to induce blocking IgG antibodies. This approach therefore offers promises for development of immunotherapeutic regimen for shrimp tropomyosin allergy. PMID:25365343

Postoperative complications of powered intracapsular tonsillectomy and monopolar electrocautery tonsillectomy in teens versus adults.

PubMed

Johnston, Douglas R; Gaslin, Michael; Boon, Maurits; Pribitkin, Edmund; Rosen, David

2010-07-01

This study was performed to determine whether teens have different rates of posttonsillectomy hemorrhage, admission for dehydration, or recurrent tonsillitis compared to adults. Specifically, these parameters were compared within two groups: patients who underwent powered intracapsular tonsillectomy (PIT) and those who underwent monopolar electrocautery tonsillectomy (MET). In a retrospective review of 579 patients at least 12 years of age from January 2000 to July 2006 in a tertiary referral center, outcome measures of reoperation for hemorrhage, readmission or emergency room visit for dehydration, and postoperative tonsillitis were compared for 200 patients 12 to 19 years of age and 379 patients more than 19 years of age. These outcome measures in teens were compared to those in adults who had tonsillectomy by the same technique (101 teens who underwent PIT compared to 117 adults who underwent PIT, and 99 teens who underwent MET compared to 262 adults who underwent MET). Outcome measures were also compared within the PIT and MET groups based on the indication for surgery (chronic tonsillitis, tonsillar hypertrophy, or both). In comparing teens to adults who underwent the same technique (PIT versus PIT, or MET versus MET), no statistically significant differences existed in the incidence of hemorrhage, dehydration, or postoperative tonsillitis. Greater hemorrhage rates for adults who underwent MET compared to teens, however, almost met statistical significance (p = 0.053). Analyzing complication rates by indication within the PIT and MET groups exclusively revealed higher rates of hemorrhage in adults who underwent the MET technique for the indication of chronic tonsillitis. Within the PIT comparison, no significant differences were found on the basis of indication for surgery. Teenage patients who undergo tonsillectomy should be considered unique as far as complication rates are concerned. Comparison of technique-specific complication rates between adults and teens showed no significant differences in either the PIT or MET groups, although adults who underwent MET had greater hemorrhage rates that almost met significance (p = 0.053). Adults who were undergoing tonsillectomy for chronic tonsillitis were more likely than teens to encounter postoperative hemorrhage if they underwent the MET technique.

[Diagnostic value of selective anorexia in pathological weight loss].

PubMed

Braquet, P; Mercier, G; Reynes, J; Jeandel, C; Pinzani, V; Guilpain, P; Rivière, S; Le Quellec, A

2016-02-01

The diagnostic value of selective anorexia is debated. Some authors have suggested an association between meat aversion and cancer, but most do not use it as a diagnostic tool. We aimed to characterize anorexia of different diseases to search for an association between selective aversions and diagnostic groups. All the patients admitted to three departments of a teaching hospital were included consecutively for 22months if they had more than 10 % weight loss in less than one year. Patients were excluded if history taking was not reliable, or if they suffered from anorexia nervosa. We compiled diagnoses at discharge and validated them six months later. We used logistic regression to identify independent factors associated with selective anorexia. Inclusion criteria were met in 106patients (female 44 %, median age 65years). Most frequent diagnoses were: cancer (36 %), infection (35 %), digestive diseases (19 %), non organic diseases (21 %). Recent selective anorexia was found in 46 % of the cases. It was significantly associated with female gender (P=0.002), marginally with young age (P=0.069) and long duration of weight loss (P=0.079). Opioid use at admission was negatively associated with selective anorexia (P=0.001). No specific diagnostic category was found to be associated. Selective anorexia does not appear to be a useful symptom to investigate pathological weight loss. It behaves more like a non-specific reactivation by current disease of earlier latent personal food aversions. Copyright © 2015 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

Prospective treatment plan-specific action limits for real-time intrafractional monitoring in surface image guided radiosurgery.

PubMed

Yock, Adam D; Pawlicki, Todd; Kim, Gwe-Ya

2016-07-01

In surface image guided radiosurgery, action limits are created to determine at what point intrafractional motion exhibited by the patient is large enough to warrant intervention. Action limit values remain constant across patients despite the fact that patient motion affects the target coverage of brain metastases differently depending on the planning technique and other treatment plan-specific factors. The purpose of this work was twofold. The first purpose was to characterize the sensitivity of single-met per iso and multimet per iso treatment plans to uncorrected patient motion. The second purpose was to describe a method to prospectively determine treatment plan-specific action limits considering this sensitivity. In their surface image guided radiosurgery technique, patient positioning is achieved with a thermoplastic mask that does not cover the patient's face. The patient's exposed face is imaged by a stereoscopic photogrammetry system. It is then compared to a reference surface and monitored throughout treatment. Seventy-two brain metastases (representing 29 patients) were used for this study. Twenty-five mets were treated individually ("single-met per iso plans"), and 47 were treated in a plan simultaneously with at least one other met ("multimet per iso plans"). For each met, the proportion of the gross tumor volume that remained within the 100% prescription isodose line was estimated under the influence of combinations of translations and rotations (0.0-3.0 mm and 0.0°-3.0°, respectively). The target volume and the prescription dose-volume were considered concentric spheres that each encompassed a volume determined from the treatment plan. Plan-specific contour plots and DVHs were created to illustrate the sensitivity of a specific lesion to uncorrected patient motion. Both single-met per iso and multimet per iso plans exhibited compromised target coverage under translations and rotations, though multimet per iso plans were considerably more sensitive to these transformations (2.3% and 39.8%, respectively). Plan-specific contour plots and DVHs were used to illustrate how size, distance from isocenter, and planning technique affect a particular met's sensitivity to motion. Stereotactic radiosurgery treatment plans that treat multiple brain metastases using a common isocenter are particularly susceptible to compromised target coverage as a result of uncorrected patient motion. The use of such a planning technique along with other treatment plan-specific factors should influence patient motion management. A graphical representation of the effect of translations and rotations on any particular plan can be generated to inform clinicians of the appropriate action limit when monitoring intrafractional motion.

Attempts to locate residues in complementarity-determining regions of antibody combining sites that make contact with antigen.

PubMed

Kabat, E A; Wu, T T; Bilofsky, H

1976-02-01

From collected data on variable region sequences of heavy chains of immunoglobulins, the probability of random associations of any two amino-acid residues in the complementarity-determining segments was computed, and pairs of residues occurring significantly more frequently than expected were selected by computer. Significant associations between Phe 32 and Tyr 33, Phe 32 and Glu 35, and Tyr 33 and Glu 35 were found in six proteins, all of which were mouse myeloma proteins which bound phosphorylcholine (= phosphocholine). From the x-ray structure of McPC603, Tyr 33 and Glu 35 are contacting residues; a seventh phosphorylcholine-binding mouse myeloma protein also contained Phe 32 and Tyr 33 but position 35 had only been determined as Glx and thus this position had not been selected. Met 34 occurred in all seven phosphorylcholine-binding myeoma proteins but was also present at this position in 29 other proteins and thus was not selected; it is seen in the x-ray structure not to be a contacting residue. The role of Phe 32 is not obvious but it could have some conformational influence. A human phosphorylcholine-binding myeloma protien also had Phe, Tyr, and Met at positions 32, 33, and 34, but had Asp instead of Glu at position 35 and showed a lower binding constant. The ability to use sequence data to locate residues in complementarity-determing segments making contact with antigenic determinants and those playing essentially a structural role would contribute substantially to the understanding of antibody specificity.

The outcome of children with selective mutism following cognitive behavioral intervention: a follow-up study.

PubMed

Lang, Claudia; Nir, Ziv; Gothelf, Ayelet; Domachevsky, Shoshi; Ginton, Lee; Kushnir, Jonathan; Gothelf, Doron

2016-04-01

Selective mutism (SM) is a relatively rare childhood disorder and is underdiagnosed and undertreated. The purpose of the retrospective naturalistic study was to examine the long-term outcome of children with SM who were treated with specifically designed modular cognitive behavioral therapy (MCBT). Parents of 36 children who met diagnostic criteria of SM that received MCBT treatment were invited for a follow-up evaluation. Parents were interviewed using structured scales and completed questionnaires regarding the child, including the Selective Mutism Questionnaire (SMQ). Twenty-four subjects were identified and evaluated. Their mean age ± SD of onset of SM symptoms, beginning of treatment, and age at follow-up were 3.4 ± 1.4, 6.4 ± 3.1, and 9.3 ± 3.4 years, respectively. There was robust improvement from beginning of treatment to follow-up evaluation in SM, social anxiety disorder, and specific phobia symptoms. The recovery rate from SM was 84.2 %. SM-focused MCBT is feasible in children and possibly effective in inducing long-term reduction of SM and comorbid anxiety symptoms. • There are limited empirical data on selective mutism (SM) treatment outcome and specifically on cognitive-behavioral therapy, with the majority of studies being uncontrolled case reports of 1 to 2 cases each. • There is also limited data on the long-term outcome of children with SM following treatment. What is New: • Modular cognitive behavioral treatment is a feasible and possibly effective treatment for SM. Intervention at a younger age is more effective comparing to an older age. • Treatment for SM also decreases the rate of psychiatric comorbidities, including separation anxiety disorder and specific phobia.

Dynamic micro- and macrovascular remodeling in coronary circulation of obese Ossabaw pigs with metabolic syndrome

PubMed Central

Katz, Paige S.; Kelly, Amy P.; Galantowicz, Maarten L.; Cismowski, Mary J.; West, T. Aaron; Neeb, Zachary P.; Berwick, Zachary C.; Goodwill, Adam G.; Alloosh, Mouhamad; Tune, Johnathan D.; Sturek, Michael; Lucchesi, Pamela A.

2012-01-01

Previous studies from our laboratory showed that coronary arterioles from type 2 diabetic mice undergo inward hypertrophic remodeling and reduced stiffness. The aim of the current study was to determine if coronary resistance microvessels (CRMs) in Ossabaw swine with metabolic syndrome (MetS) undergo remodeling distinct from coronary conduit arteries. Male Ossabaw swine were fed normal (n = 7, Lean) or hypercaloric high-fat (n = 7, MetS) diets for 6 mo, and then CRMs were isolated and mounted on a pressure myograph. CRMs isolated from MetS swine exhibited decreased luminal diameters (126 ± 5 and 105 ± 9 μm in Lean and MetS, respectively, P < 0.05) with thicker walls (18 ± 3 and 31 ± 3 μm in Lean and MetS, respectively, P < 0.05), which doubled the wall-to-lumen ratio (14 ± 2 and 30 ± 2 in Lean and MetS, respectively, P < 0.01). Incremental modulus of elasticity (IME) and beta stiffness index (BSI) were reduced in CRMs isolated from MetS pigs (IME: 3.6 × 106 ± 0.7 × 106 and 1.1 × 106 ± 0.2 × 106 dyn/cm2 in Lean and MetS, respectively, P < 0.001; BSI: 10.3 ± 0.4 and 7.3 ± 1.8 in Lean and MetS, respectively, P < 0.001). BSI in the left anterior descending coronary artery was augmented in pigs with MetS. Structural changes were associated with capillary rarefaction, decreased hyperemic-to-basal coronary flow velocity ratio, and augmented myogenic tone. MetS CRMs showed a reduced collagen-to-elastin ratio, while immunostaining for the receptor for advanced glycation end products was selectively increased in the left anterior descending coronary artery. These data suggest that MetS causes hypertrophic inward remodeling of CRMs and capillary rarefaction, which contribute to decreased coronary flow and myocardial ischemia. Moreover, our data demonstrate novel differential remodeling between coronary micro- and macrovessels in a clinically relevant model of MetS. PMID:22837170

Independent and joint associations of TV viewing time and snack food consumption with the metabolic syndrome and its components; a cross-sectional study in Australian adults

PubMed Central

2013-01-01

Background Television (TV) viewing time is positively associated with the metabolic syndrome (MetS) in adults. However, the mechanisms through which TV viewing time is associated with MetS risk remain unclear. There is evidence that the consumption of energy-dense, nutrient poor snack foods increases during TV viewing time among adults, suggesting that these behaviors may jointly contribute towards MetS risk. While the association between TV viewing time and the MetS has previously been shown to be independent of adult’s overall dietary intake, the specific influence of snack food consumption on the relationship is yet to be investigated. The purpose of this study was to examine the independent and joint associations of daily TV viewing time and snack food consumption with the MetS and its components in a sample of Australian adults. Methods Population-based, cross-sectional study of 3,110 women and 2,572 men (>35 years) without diabetes or cardiovascular disease. Participants were recruited between May 1999 and Dec 2000 in the six states and the Northern Territory of Australia. Participants were categorised according to self-reported TV viewing time (low: 0-2 hr/d; high: >2 hr/d) and/or consumption of snack foods (low: 0-3 serves/d; high: >3 serves/d). Multivariate odds ratios [95% CI] for the MetS and its components were estimated using gender-specific, forced entry logistic regression. Results OR [95% CI] for the MetS was 3.59 [2.25, 5.74] (p≤0.001) in women and 1.45 [1.02, 3.45] (p = 0.04) in men who jointly reported high TV viewing time and high snack food consumption. Obesity, insulin resistance and hypertension (women only) were also jointly associated with high TV viewing time and high snack food consumption. Further adjustment for diet quality and central adiposity maintained the associations in women. High snack food consumption was also shown to be independently associated with MetS risk [OR: 1.94 (95% CI: 1.45, 2.60), p < 0.001] and hypertension [OR: 1.43 (95% CI: 1.01, 2.02), p = 0.05] in women only. For both men and women, high TV viewing time was independently associated with the MetS and its individual components (except hypertension). Conclusion TV viewing time and snack food consumption are independently and jointly associated with the MetS and its components, particularly in women. In addition to physical activity, population strategies targeting MetS prevention should address high TV time and excessive snack food intake. PMID:23927043

Independent and joint associations of TV viewing time and snack food consumption with the metabolic syndrome and its components; a cross-sectional study in Australian adults.

PubMed

Thorp, Alicia A; McNaughton, Sarah A; Owen, Neville; Dunstan, David W

2013-08-09

Television (TV) viewing time is positively associated with the metabolic syndrome (MetS) in adults. However, the mechanisms through which TV viewing time is associated with MetS risk remain unclear. There is evidence that the consumption of energy-dense, nutrient poor snack foods increases during TV viewing time among adults, suggesting that these behaviors may jointly contribute towards MetS risk. While the association between TV viewing time and the MetS has previously been shown to be independent of adult's overall dietary intake, the specific influence of snack food consumption on the relationship is yet to be investigated. The purpose of this study was to examine the independent and joint associations of daily TV viewing time and snack food consumption with the MetS and its components in a sample of Australian adults. Population-based, cross-sectional study of 3,110 women and 2,572 men (>35 years) without diabetes or cardiovascular disease. Participants were recruited between May 1999 and Dec 2000 in the six states and the Northern Territory of Australia. Participants were categorised according to self-reported TV viewing time (low: 0-2 hr/d; high: >2 hr/d) and/or consumption of snack foods (low: 0-3 serves/d; high: >3 serves/d). Multivariate odds ratios [95% CI] for the MetS and its components were estimated using gender-specific, forced entry logistic regression. OR [95% CI] for the MetS was 3.59 [2.25, 5.74] (p≤0.001) in women and 1.45 [1.02, 3.45] (p = 0.04) in men who jointly reported high TV viewing time and high snack food consumption. Obesity, insulin resistance and hypertension (women only) were also jointly associated with high TV viewing time and high snack food consumption. Further adjustment for diet quality and central adiposity maintained the associations in women. High snack food consumption was also shown to be independently associated with MetS risk [OR: 1.94 (95% CI: 1.45, 2.60), p < 0.001] and hypertension [OR: 1.43 (95% CI: 1.01, 2.02), p = 0.05] in women only. For both men and women, high TV viewing time was independently associated with the MetS and its individual components (except hypertension). TV viewing time and snack food consumption are independently and jointly associated with the MetS and its components, particularly in women. In addition to physical activity, population strategies targeting MetS prevention should address high TV time and excessive snack food intake.

Detection of Met-enkephalin and Leu-enkephalin in the posterior pituitary of the holostean fish, Amia calva.

PubMed

Dores, R M; McDonald, L K; Crim, J W

1989-01-01

Immunohistochemical analysis of the pituitary of the holostean fish, Amia calva, indicated that enkephalin-related immunoreactivity was restricted to the pars nervosa, and was not detected in other regions of the pituitary. Fractionation of acid extracts of posterior pituitaries by reverse phase HPLC followed by RIA analysis indicated the presence of immunoreactive Met-enkephalin and Leu-enkephalin. No immunoreactive forms were detected with RIAs specific for either Met-enkephalin-RF or Met-enkephalin-RGL. The molar ratio of Met- to Leu-enkephalin in this terminal field was 3:1 (n = 4). HPLC fractions were also digested with trypsin and carboxypeptidase B to test for C-terminally extended forms of Met-enkephalin. A novel modified form of Met-enkephalin was detected. Extracts of the posterior pituitary, forebrain, midbrain, hypothalamus and hindbrain were screened with RIAs specific for the Pro-dynorphin end products, alpha-neo-endorphin, dynorphin A(1-17), dynorphin A(1-8) and dynorphin B(1-13). The results of these analyses were negative. Collectively, these data suggest that a Pro-enkephalin-like molecule is present in holostean fish. The holostean enkephalin precursor contains at least Met-enkephalin and Leu-enkephalin. However, Pro-dynorphin-related end products with antigenic determinants similar to mammalian dynorphin A(1-17), dynorphin A(1-8), dynorphin B(1-13) and alpha-neo-endorphin could not be detected in the brain or pituitary of this species.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dobromir Panayotov; Andrew Grief; Brad J. Merrill

'Fusion for Energy' (F4E) develops designs and implements the European Test Blanket Systems (TBS) in ITER - Helium-Cooled Lithium-Lead (HCLL) and Helium-Cooled Pebble-Bed (HCPB). Safety demonstration is an essential element for the integration of TBS in ITER and accident analyses are one of its critical segments. A systematic approach to the accident analyses had been acquired under the F4E contract on TBS safety analyses. F4E technical requirements and AMEC and INL efforts resulted in the development of a comprehensive methodology for fusion breeding blanket accident analyses. It addresses the specificity of the breeding blankets design, materials and phenomena and atmore » the same time is consistent with the one already applied to ITER accident analyses. Methodology consists of several phases. At first the reference scenarios are selected on the base of FMEA studies. In the second place elaboration of the accident analyses specifications we use phenomena identification and ranking tables to identify the requirements to be met by the code(s) and TBS models. Thus the limitations of the codes are identified and possible solutions to be built into the models are proposed. These include among others the loose coupling of different codes or code versions in order to simulate multi-fluid flows and phenomena. The code selection and issue of the accident analyses specifications conclude this second step. Furthermore the breeding blanket and ancillary systems models are built on. In this work challenges met and solutions used in the development of both MELCOR and RELAP5 codes models of HCLL and HCPB TBSs will be shared. To continue the developed models are qualified by comparison with finite elements analyses, by code to code comparison and sensitivity studies. Finally, the qualified models are used for the execution of the accident analyses of specific scenario. When possible the methodology phases will be illustrated in the paper by limited number of tables and figures. Description of each phase and its results in detail as well the methodology applications to EU HCLL and HCPB TBSs will be published in separate papers. The developed methodology is applicable to accident analyses of other TBSs to be tested in ITER and as well to DEMO breeding blankets.« less

Biology of MET: a double life between normal tissue repair and tumor progression

PubMed Central

2015-01-01

MNNG HOS transforming gene (MET) is a class IV receptor tyrosine kinase, expressed on the surface of epithelial cells. The interaction with the hepatocyte grow factor (HGF) induces MET dimerization and the activation of multiple intracellular pathways leading to cell proliferation, anti-apoptosis, morphogenic differentiation, motility, invasion, and angiogenesis. Knock out mice have demonstrated that MET is necessary for normal embryogenesis including the formation of striate muscles, liver and trophoblastic structures. The overexpression of MET and HGF are common in solid tumors and contribute to determine their growth. Indeed, MET has been cloned as a transforming gene from a chemically induced human osteosarcoma cell line and therefore is considered a proto-oncogene. Germline MET mutations are characteristic of hereditary papillary kidney cancers and MET amplification is observed in tumors including lung and gastric adenocarcinomas. The inhibition of MET signaling is the target for specific drugs that are raising exciting expectation for medical treatment of cancer. PMID:25992381

The MET/AXL/FGFR Inhibitor S49076 Impairs Aurora B Activity and Improves the Antitumor Efficacy of Radiotherapy.

PubMed

Clémenson, Céline; Chargari, Cyrus; Liu, Winchygn; Mondini, Michele; Ferté, Charles; Burbridge, Mike F; Cattan, Valérie; Jacquet-Bescond, Anne; Deutsch, Eric

2017-10-01

Several therapeutic agents targeting HGF/MET signaling are under clinical development as single agents or in combination, notably with anti-EGFR therapies in non-small cell lung cancer (NSCLC). However, despite increasing data supporting a link between MET, irradiation, and cancer progression, no data regarding the combination of MET-targeting agents and radiotherapy are available from the clinic. S49076 is an oral ATP-competitive inhibitor of MET, AXL, and FGFR1-3 receptors that is currently in phase I/II clinical trials in combination with gefitinib in NSCLC patients whose tumors show resistance to EGFR inhibitors. Here, we studied the impact of S49076 on MET signaling, cell proliferation, and clonogenic survival in MET-dependent (GTL16 and U87-MG) and MET-independent (H441, H460, and A549) cells. Our data show that S49076 exerts its cytotoxic activity at low doses on MET-dependent cells through MET inhibition, whereas it inhibits growth of MET-independent cells at higher but clinically relevant doses by targeting Aurora B. Furthermore, we found that S49076 improves the antitumor efficacy of radiotherapy in both MET-dependent and MET-independent cell lines in vitro and in subcutaneous and orthotopic tumor models in vivo In conclusion, our study demonstrates that S49076 has dual antitumor activity and can be used in combination with radiotherapy for the treatment of both MET-dependent and MET-independent tumors. These results support the evaluation of combined treatment of S49076 with radiation in clinical trials without patient selection based on the tumor MET dependency status. Mol Cancer Ther; 16(10); 2107-19. ©2017 AACR . ©2017 American Association for Cancer Research.

Correlation among genetic variations of c-MET in Chinese patients with non-small cell lung cancer.

PubMed

Duan, Jianchun; Yang, Xiaodan; Zhao, Jun; Zhuo, Minglei; Wang, Zhijie; An, Tongtong; Bai, Hua; Wang, Jie

2018-01-05

The purpose of our research was to determine the correlation of amplification, protein expression and somatic mutation of c-MET in IIIb-IV stage NSCLC (Non-small cell lung cancer). We also explored correlation of c-MET variation with clinical outcome. c-MET expression was observed in 28.6% (56/196) cases, and among those 13.8% (27/196) were shown to be FISH positive. Only 2.67% patients in this study carried the c-MET mutation. Cases with c-MET FISH positive were all IHC positive ,but in IHC positive cases, only half were FISH positive. Among patients with IHC 2+ staining, 35.5% was FISH positive, while cases with IHC 3+ staining,64% was FISH positive. Both protein expression and copy number of c-MET did not significantly correlate with clinical prognosis in these patients treated with EGFR-TKIs. IHC could be used as a preliminary screening method for c-MET copy number amplification and should be confirmed by FISH only in IHC positive case which facilitate selection of ALK or MET inhibitor therapy. c-MET gene copy number, protein expression and somatic mutation for exon 14 were detected by fluorescent- In-Situ -Hybridization (FISH), Immunohistochemistry (IHC), and Denaturing-High-Performance-Liquid-Chromatography (DHPLC), respectively, in 196 NSCLC patients. The relationship between c-MET abnormalities and clinical outcome of targeted therapy was analyzed by McNemar's test.

Metabolic Syndrome in Male Hypogonadism.

PubMed

Rastrelli, Giulia; Filippi, Sandra; Sforza, Alessandra; Maggi, Mario; Corona, Giovanni

2018-01-01

Metabolic syndrome (MetS) and hypogonadism (HG) are frequently comorbid. In this review, we summarize interconnections between the construct of MetS and the presence of HG, as well as the effect of specific treatments for each condition on this association. Data from meta-analytic studies suggest a bidirectional pathogenic relationship. In fact, reduced T (-2.21 [-2.43 to -1.98] nmol/L) at baseline predicts incident MetS. On the other hand, MetS at study entry increases the risk of developing HG (OR 2.46 [1.77-3.42]). The bidirectional pathogenic link between MetS and HG is further confirmed by the fact that treating MetS with insulin sensitizer is associated with an increase in T. In addition, a huge effect on increasing T is found in obese men undergoing procedures for losing weight, with more dramatic results obtained after bariatric surgery than after low calorie diet (increase in T 8.73 [6.51-10.95] nmol/L and 2.87 [1.68-4.07] nmol/L, respectively, according to a recent meta-analysis). On the other hand, there is evidence of an improvement in several metabolic derangements characterizing MetS in subjects treated with T. However, the latter results are still not conclusive and need further evidence from randomized clinical trials. © 2018 S. Karger AG, Basel.

An update on the prevalence of metabolic syndrome and its associated factors in rural northeast China.

PubMed

Yu, Shasha; Guo, Xiaofan; Yang, Hongmei; Zheng, Liqiang; Sun, Yingxian

2014-08-26

The last study reported the prevalence of Metabolic Syndrome (MetS) in rural Northeast China was conducted approximately ten years ago. We aimed to update the data on the prevalence and epidemiological features of MetS in rural Northeast China. This survey was conducted from July 2012 to August 2013. In this study, a total of 11,496 residents from the rural Northeast China were randomly selected and examined. MetS was defined according to the ATPIII-modified criteria. Data regarding the demographic and lifestyle characteristics and the blood biochemical indexes of these participants were collected by well-trained personnel. The prevalence of MetS was 39.0% and was more prevalent in women than in men (45.6% vs. 31.4%, P < 0.001). Elevated blood pressure was the most common metabolic disorder in both genders (71.7% in males and 63.3% in females). Only 11.2% and 9.6% of males and females, respectively, in this study had no metabolic disorders. Multivariate logistic regression, after adjusting for possible confounders, revealed the following factors that increased the risk of MetS: being female, older age, having more than one child, a family income of >20,000 CNY per year, longer sleep duration (>9 h/d), chronic disease status, frequent consumption of beans or bean products and frequent tea drinking. Completion of education through middle school, moderate physical activity and smoking were correlated with lower rates of MetS. The prevalence of MetS was high in the rural areas of China, especially among females. In addition to some of the more conventional risk factors associated with MetS, including age, sex, annual income and educational status, we also found that having more than one child and frequent consumption of tea and beans were risk factors for MetS, while smoking was a common factor among those that did not have MetS in rural Northeast China.

Evaluation of Monocyte to High-Density Lipoprotein Cholesterol Ratio in the Presence and Severity of Metabolic Syndrome.

PubMed

Uslu, Ali Ugur; Sekin, Yahya; Tarhan, Gulten; Canakcı, Nuray; Gunduz, Mehmet; Karagulle, Mustafa

2017-01-01

Monocyte to high-density lipoprotein cholesterol ratio (MHR) is a systemic inflammatory marker, and recently, it has been used quite commonly for the assessment of inflammation in cardiovascular disorders. The aim of the present study is to investigate the relevance of MHR as a marker to assess metabolic syndrome (MetS) and MetS severity in clinical practice. A total of 147 patients with MetS who were diagnosed according to National Cholesterol Education Program Adult Treatment Panel III criteria and 134 healthy controls, matched for age and gender, were included in our retrospective study. MHR values were 13.15 ± 6.07 for patients with MetS and 9.74 ± 5.24 for the control group. MHR values of the patients were found to be statistically significantly higher than the control group ( P < .0001). MHR showed a significantly positive correlation with the severity of MetS ( r = .429; P < .0001). When patients with MetS were assessed with MHR in the study population, receiver-operating characteristic curve analysis yielded a cutoff value of 9.36 with a sensitivity of 72%, a specificity of 61%, and a P value <.0001. In logistic regression analyses of MetS with several variables, MHR remained as an independent predictor of MetS (95% CI: 0.721-0.945, P = .005). MHR might be an available and useful inflammatory marker to evaluate patients with MetS and disease severity.

Association of metabolic syndrome risk factors with selected markers of oxidative status and microinflammation in healthy omnivores and vegetarians.

PubMed

Sebeková, Katarína; Boor, Peter; Valachovicová, Martina; Blazícek, Pavol; Parrák, Vojtech; Babinská, Katarína; Heidland, August; Krajcovicová-Kudlácková, Marica

2006-09-01

Conditions predisposing to metabolic syndrome (MetS) are associated with increased oxidative stress and inflammation. We studied, in vegetarians (n = 90) and omnivores (n = 46), the impact of the dietary regimen on the occurrence of MetS risk factors (RFs: BMI, blood pressure, glucose metabolism and lipid profile) in relation to oxidative status (advanced glycation end products (AGEs), advanced oxidation protein products (AOPPs), malondialdehyde, ferric reducing ability of plasma, vitamins A, E, C, beta-carotene and superoxide dismutase activity) and microinflammation (C-reactive protein, leukocytes and neopterin). The proportion of subjects without/positive for one or two MetS RFs was comparable between the groups. From the components of MetS only immunoreactive insulin levels differed significantly (95% CI: omnivores: 5.0-7.1 microU/mL, vegetarians: 4.5-5.4, p = 0.03). Omnivores had lower AOPP (omnivores: 0.29-0.36 micromol/g albumin, vegetarians: 0.36-0.52, p = 0.01) and beta-carotene levels than vegetarians, they consumed more calories, proteins, fat and saturated fatty acids, and less fibres, beta-carotene and vitamin C. Multiple regression analysis revealed vitamin E and AOPP levels as the most important independent determinants of MetS RFs. The vegetarian diet seems to exert beneficial effects on MetS RFs associated microinflammation. Whether the vegetarian diet may counteract the deleterious effects of elevated AOPPs and AGEs, remains to be elucidated.

Dietary Strategies Implicated in the Prevention and Treatment of Metabolic Syndrome

PubMed Central

de la Iglesia, Rocio; Loria-Kohen, Viviana; Zulet, Maria Angeles; Martinez, Jose Alfredo; Reglero, Guillermo; Ramirez de Molina, Ana

2016-01-01

Metabolic syndrome (MetS) is established as the combination of central obesity and different metabolic disturbances, such as insulin resistance, hypertension and dyslipidemia. This cluster of factors affects approximately 10%–50% of adults worldwide and the prevalence has been increasing in epidemic proportions over the last years. Thus, dietary strategies to treat this heterogenic disease are under continuous study. In this sense, diets based on negative-energy-balance, the Mediterranean dietary pattern, n-3 fatty acids, total antioxidant capacity and meal frequency have been suggested as effective approaches to treat MetS. Furthermore, the type and percentage of carbohydrates, the glycemic index or glycemic load, and dietary fiber content are some of the most relevant aspects related to insulin resistance and impaired glucose tolerance, which are important co-morbidities of MetS. Finally, new studies focused on the molecular action of specific nutritional bioactive compounds with positive effects on the MetS are currently an objective of scientific research worldwide. The present review summarizes some of the most relevant dietary approaches and bioactive compounds employed in the treatment of the MetS to date. PMID:27834920

Does presence of metabolic syndrome impact anxiety and depressive disorder screening results in middle aged and elderly individuals? A population based study.

PubMed

Butnoriene, Jurate; Steibliene, Vesta; Saudargiene, Ausra; Bunevicius, Adomas

2018-01-08

Depressive and anxiety disorders are common in primary care setting but often remain undiagnosed. Metabolic syndrome (MetS) is also prevalent in the general population and can impair recognition of common mental disorders due to significant co-morbidity and overlap with psychiatric symptoms included in self-reported depression/anxiety screening tools. We investigated if MetS has an impact on the accuracy of current major depressive disorder (MDD) and generalized anxiety disorder (GAD) screening results using the Hospital Anxiety and Depression scale (HADS). A total of 1115 (562 men; mean age 62.0 ± 9.6 years) individuals of 45+ years of age were randomly selected from the general population and evaluated for current MetS; depressive and anxiety symptoms (HADS); and current MDD and GAD (Mini International Neuropsychiatric Interview [MINI]). The MetS was diagnosed in 34.4% of the study participants. Current MDD and GAD were more common in individuals with MetS relative to individuals without MetS (25.3% vs 14.2%, respectively, p < 0.001; and 30.2% vs 20.9%, respectively, p < 0.001). The ROC analyses demonstrated that optimal thresholds of the HADS-Depression subscale for current MDE were ≥9 in individuals with MetS (sensitivity = 87%, specificity = 73% and PPV = 52%) and ≥8 in individuals without MetS (sensitivity = 81%, specificity = 78% and PPV = 38%). At threshold of ≥9 the HADS-Anxiety subscale demonstrated optimal psychometric properties for current GAD screening in individuals with MetS (sensitivity = 91%, specificity = 85% and PPV = 72%) and without MetS (sensitivity = 84%, specificity = 83% and PPV = 56%). The HADS is a reliable screening tool for current MDE and GAD in middle aged and elderly population with and without MetS. Optimal thresholds of the HADS-Depression subscale for current MDD is ≥9 for individuals with MetS and ≥8 - without MetS. Optimal threshold of the HADS-Anxiety subscale is ≥9 for current GAD in individuals with and without MetS. The presence of MetS should be considered when interpreting depression screening results.

Depressive Symptoms and Metabolic Syndrome: Is Inflammation the Underlying Link?

PubMed Central

Capuron, Lucile; Su, Shaoyong; Miller, Andrew H.; Bremner, J. Douglas; Goldberg, Jack; Vogt, Gerald J.; Maisano, Carisa; Jones, Linda; Murrah, Nancy V.; Vaccarino, Viola

2008-01-01

Background Behavioral alterations, including depression, are frequent in individuals with the metabolic syndrome (MetS). Recent findings suggest that chronic activation of innate immunity may be involved. The objective of this study was to examine the relationship between MetS and depressive symptoms and to elucidate the involvement of inflammation in this relationship. Methods Participants were 323 male twins, with and without MetS and free of symptomatic cardiovascular disease, drawn from the Vietnam-Era-Twin Registry. Depressive symptoms were measured with the Beck-Depression-Inventory (BDI). Inflammatory status was assessed using C-reactive protein (CRP) and interleukin-6 (IL-6); twins with both CRP and IL-6 levels above the median were classified as having an elevated inflammatory status. Factor analysis was performed on individual BDI items to extract specific symptom dimensions (neurovegetative, mood, affective-cognitive). Results Subjects with MetS had more depressive symptoms than those without. Depressive symptoms with neurovegetative features were more common and more robustly associated with MetS. Both the BDI total score and each symptom subscore were associated with inflammatory biomarkers. After adjusting for age, education and smoking status, the MetS was significantly associated with the BDI total score and the neurovegetative score. After further adjusting for inflammation, the coefficient for MetS decreased somewhat, but remained statistically significant for the BDI neurovegetative subscore. When controlling for the MetS, inflammation remained significantly associated with the BDI mood subscore. Conclusions The MetS is associated with higher depressive symptomatology characterized primarily by neurovegetative features. Inflammation is one determinant of depressive symptoms in individuals with MetS. PMID:18597739

Carotid Plaque Morphology in Asymptomatic Patients with and without Metabolic Syndrome.

PubMed

Cury, Marcus Vinícius Martins; Presti, Calógero; Bonadiman, Suellen Stevam Timotheo; Casella, Ivan Benaduce; Benabou, Joseph Elias; da Silva, Erasmo Simão; de Luccia, Nelson; Puech-Leão, Pedro

2017-02-01

The aim of this study was to determine the impact of metabolic syndrome (MetS) on the morphology of carotid plaques, as evaluated using duplex ultrasound (DUS) with computer-assisted analysis. In this cross-sectional observational study, we analyzed 148 carotid artery plaques in asymptomatic patients. Data were obtained via clinical and laboratory examinations, and DUS was performed by a single operator. All plaques were scanned in a longitudinal fashion, and the best segment was selected, recorded, and evaluated using dedicated software. The main software-based analyses included gray-scale median (GSM) measurements and carotid plaque morphology histograms. MetS was identified in 51.8% of patients. Comparisons of patients with MetS and patients without MetS indicated that the former patients used more classes of antihypertensive drugs (2.49 vs. 1.93; P = 0.004) and were treated with statins for a longer period (71.08 vs. 49.17 months; P = 0.003). Most patients of both types exhibited moderate carotid artery stenosis ranging from 50% to 69% (n = 62; 37.3%), and MetS was not associated with an increased prevalence of severe carotid artery stenosis. The mean GSM was greater in the MetS group than in the non-MetS group (74.18 vs. 61.63; P = 0.012). The histogram analysis revealed that there were lower quantities of blood and fat (2.91 vs. 3.88; P = 0.006; 10.21 vs. 15.08; P = 0.004, respectively) and more fibrous tissue (19.93 vs. 14.55; P = 0.015) in the carotid plaques of patients with MetS than in the carotid plaques of patients without MetS. The present study demonstrated that MetS did not affect the stenosis grade or did it lead to unstable carotid plaques. Copyright © 2016 Elsevier Inc. All rights reserved.

Comparative genomics of transcriptional regulation of methionine metabolism in proteobacteria

DOE PAGES

Leyn, Semen A.; Suvorova, Inna A.; Kholina, Tatiana D.; ...

2014-11-20

Methionine metabolism and uptake genes in Proteobacteria are controlled by a variety of RNA and DNA regulatory systems. We have applied comparative genomics to reconstruct regulons for three known transcription factors, MetJ, MetR, and SahR, and three known riboswitch motifs, SAH, SAM-SAH, and SAM_alpha, in ~200 genomes from 22 taxonomic groups of Proteobacteria. We also identified two novel regulons: a SahR-like transcription factor SamR controlling various methionine biosynthesis genes in the Xanthomonadales group, and a potential RNA regulatory element with terminator-antiterminator mechanism controlling the metX or metZ genes in beta-proteobacteria. For each analyzed regulator we identified the core, taxon-specific andmore » genome-specific regulon members. By analyzing the distribution of these regulators in bacterial genomes and by comparing their regulon contents we elucidated possible evolutionary scenarios for the regulation of the methionine metabolism genes in Proteobacteria.« less

The relationship between metabolic syndrome, its components, and erectile dysfunction: a systematic review and a meta-analysis of observational studies.

PubMed

Besiroglu, Huseyin; Otunctemur, Alper; Ozbek, Emin

2015-06-01

The studies examining the association between metabolic syndrome (MetS), its components, and erectile dysfunction (ED) should be reevaluated to arrive at comprehensive results in this field. Our aim was to gather individual studies in order to achieve a more reliable conclusion regarding the relationship between MetS, its components, and ED. Three investigators searched the Pubmed-Medline and Embase databases using the key words "metabolic syndrome" and "erectile dysfunction." The individual studies were evaluated for selection of suitable studies. Eight studies that met all inclusion criteria were chosen, and a pooled analysis of odds ratio (ORs) between MetS and ED was calculated. The components of MetS to ED were also estimated. Eight observational studies with a total of 12,067 participants were examined. The overall analysis revealed a 2.6-fold increase in patients with MetS having ED (2.67[1.79-3.96]; P < 0.0001). All individual components of MetS except high-density lipoprotein level were also found to correlate with an increased prevalence of ED. Of those, fasting blood sugar was detected highest rate for ED with OR of 2.07 ([1.49-2.87]; P < 0.0001). Metabolic syndrome is associated with a high risk rate of ED, and patients with MetS should be informed about this association and encouraged to make lifestyle modifications to improve their general health and to limit cardiovascular risk as well as ED prevalence. However, manuscripts included in meta-analysis were observational studies that prohibits ascertainment of temporal associations and necessitates further prospective studies. © 2015 International Society for Sexual Medicine.

Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma and its association with PD-L1 expression.

PubMed

Lalani, Aly-Khan A; Gray, Kathryn P; Albiges, Laurence; Callea, Marcella; Pignon, Jean-Christophe; Pal, Soumitro; Gupta, Mamta; Bhatt, Rupal S; McDermott, David F; Atkins, Michael B; Woude, G F Vande; Harshman, Lauren C; Choueiri, Toni K; Signoretti, Sabina

2017-11-28

In preclinical models, c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). However, this relationship in human clear cell renal cell carcinoma (ccRCC) is not well characterized. We evaluated c-Met expression in ccRCC patients using paired primary and metastatic samples and assessed the association with PD-L1 expression and other clinical features. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab) and calculated by a combined score (CS, 0-300): intensity of c-Met staining (0-3) x % of positive cells (0-100). PD-L1 expression in tumor cells was previously assessed by IHC and PD-L1+ was defined as PD-L1 > 0% positive cells. Our cohort consisted of 45 pairs of primary and metastatic ccRCC samples. Overall, c-Met expression was higher in metastatic sites compared to primary sites (average c-Met CS: 55 vs. 28, p = 0.0003). Higher c-Met expression was associated with higher FNG (4 vs. 3) in primary tumors (average c-Met CS: 52 vs. 20, p = 0.04). c-Met expression was numerically greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression in metastatic sites compared to primary tumors suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. While higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination clinical trials.

Systematic review of systemic sclerosis-specific instruments for the EULAR Outcome Measures Library: An evolutional database model of validated patient-reported outcomes.

PubMed

Ingegnoli, Francesca; Carmona, Loreto; Castrejon, Isabel

2017-04-01

The EULAR Outcome Measures Library (OML) is a freely available database of validated patient-reported outcomes (PROs). The aim of this study was to provide a comprehensive review of validated PROs specifically developed for systemic sclerosis (SSc) to feed the EULAR OML. A sensitive search was developed in Medline and Embase to identify all validation studies, cohort studies, reviews, or meta-analyses in which the objective were the development or validation of specific PROs evaluating organ involvement, disease activity or damage in SSc. A reviewer screened title and abstracts, selected the studies, and collected data concerning validation using ad hoc forms based on the COSMIN checklist. From 13,140 articles captured, 74 met the predefined criteria. After excluding two instruments as they were unavailable in English the selected 23 studies provided information on seven SSc-specific PROs on different SSc domains: burden of illness (symptom burden index), functional status (Scleroderma Assessment Questionnaire), functional ability (scleroderma Functional Score), Raynaud's phenomenon (Raynaud's condition score), mouth involvement (Mouth Handicap in SSc), gastro-intestinal involvement (University of California Los Angeles-Scleroderma Clinical Trial Consortium Gastro-Intestinal tract 2.0), and skin involvement (skin self-assessment). Each of them is partially validated and has different psychometric requirements. Seven SSc-specific PROs have a minimum validation and were included in the EULAR OML. Further development in the area of disease-specific PROs in SSc is warranted. Copyright © 2017 Elsevier Inc. All rights reserved.

Dissection of combinatorial control by the Met4 transcriptional complex.

PubMed

Lee, Traci A; Jorgensen, Paul; Bognar, Andrew L; Peyraud, Caroline; Thomas, Dominique; Tyers, Mike

2010-02-01

Met4 is the transcriptional activator of the sulfur metabolic network in Saccharomyces cerevisiae. Lacking DNA-binding ability, Met4 must interact with proteins called Met4 cofactors to target promoters for transcription. Two types of DNA-binding cofactors (Cbf1 and Met31/Met32) recruit Met4 to promoters and one cofactor (Met28) stabilizes the DNA-bound Met4 complexes. To dissect this combinatorial system, we systematically deleted each category of cofactor(s) and analyzed Met4-activated transcription on a genome-wide scale. We defined a core regulon for Met4, consisting of 45 target genes. Deletion of both Met31 and Met32 eliminated activation of the core regulon, whereas loss of Met28 or Cbf1 interfered with only a subset of targets that map to distinct sectors of the sulfur metabolic network. These transcriptional dependencies roughly correlated with the presence of Cbf1 promoter motifs. Quantitative analysis of in vivo promoter binding properties indicated varying levels of cooperativity and interdependency exists between members of this combinatorial system. Cbf1 was the only cofactor to remain fully bound to target promoters under all conditions, whereas other factors exhibited different degrees of regulated binding in a promoter-specific fashion. Taken together, Met4 cofactors use a variety of mechanisms to allow differential transcription of target genes in response to various cues.

Relationships between 24-hour urinary free cortisol concentrations and metabolic syndrome in obese children.

PubMed

Reinehr, Thomas; Kulle, Alexandra; Wolters, Barbara; Knop, Caroline; Lass, Nina; Welzel, Maik; Holterhus, Paul-Martin

2014-07-01

Clinical features of Metabolic Syndrome (MetS) and Cushing's Syndrome are similar, suggesting a pathogenetic role of hypothalamus-pituitary-adrenal axis in MetS. The aim of the study was to determine whether MetS diagnosis and specific clusters of MetS components (waist circumference, dyslipidemia, hypertension, and impaired glucose metabolism) are associated with serum cortisol (SC) or 24-h urinary free cortisol (UFC) levels. We conducted cross-sectional analyses of data from our obesity cohort. We studied 264 obese children (age, 11.0 ± 2.8 years; male, 48%; BMI, 28.2 ± 5.4 kg/m(2)). We examined UFC, SC, homeostasis model assessment (HOMA), and features of MetS (waist circumference, blood pressure, fasting lipids, and glucose). Slightly increased UFC concentrations were measured in 30.7% of the children. Obese children with MetS had significantly (P = .003) higher UFC levels compared with obese children without MetS. Girls demonstrated significantly higher UFC concentrations compared with boys independent of pubertal stage. UFC and SC levels were significantly related to features of MetS, but the associations were stronger for UFC. In multivariate analyses adjusted for age, sex, and body mass index, none of the features of MetS but HOMA index was correlated with UFC, whereas SC demonstrated no significant association to any parameter of MetS or HOMA. Our findings support the hypothesis that changes in the hypothalamus-pituitary-adrenal axis are related to MetS in obesity. UFC seems to be a suitable marker for this relationship. Norm values for UFC adapted to obese children may help to avoid unnecessary dexamethasone suppression tests.

In vivo levels of S-adenosylmethionine modulate C:G to T:A mutations associated with repeat-induced point mutation in Neurospora crassa.

PubMed

Rosa, Alberto Luis; Folco, Hernán Diego; Mautino, Mario Ricardo

2004-04-14

In Neurospora crassa, the mutagenic process termed repeat-induced point mutation (RIP) inactivates duplicated DNA sequences during the sexual cycle by the introduction of C:G to T:A transition mutations. In this work, we have used a collection of N. crassa strains exhibiting a wide range of cellular levels of S-adenosylmethionine (AdoMet), the universal donor of methyl groups, to explore whether frequencies of RIP are dependent on the cellular levels of this metabolite. Mutant strains met-7 and eth-1 carry mutations in genes of the AdoMet pathway and have low levels of AdoMet. Wild type strains with high levels of AdoMet were constructed by introducing a chimeric transgene of the AdoMet synthetase (AdoMet-S) gene fused to the constitutive promoter trpC from Aspergillus nidulans. Crosses of these strains against tester duplications of the pan-2 and am genes showed that frequencies of RIP, as well as the total number of C:G to T:A transition mutations found in randomly selected am(RIP) alleles, are inversely correlated to the cellular level of AdoMet. These results indicate that AdoMet modulates the biochemical pathway leading to RIP.

The role of probiotics on each component of the metabolic syndrome and other cardiovascular risks.

PubMed

Miglioranza Scavuzzi, Bruna; Miglioranza, Lucia Helena da Silva; Henrique, Fernanda Carla; Pitelli Paroschi, Thanise; Lozovoy, Marcell Alysson Batisti; Simão, Andréa Name Colado; Dichi, Isaias

2015-01-01

Probiotics are defined as live microorganisms that when administered in adequate amounts confer health benefits to the host. The consumption of probiotics has gained increasing recognition from the scientific community due to the promising effects on metabolic health through gut microbiota modulation. This article presents a review of scientific studies investigating probiotic species and their effects on different risk factors of the metabolic syndrome (MetS). This article also presents a summary of the major mechanisms involved with gut microbiota and the components of the MetS and raises the key issues to be considered by scientists in search of probiotics species for treatment of patients suffering from this metabolic disorder. Probiotics may confer numerous health benefits to the host through positive gut microbiota modulation. The strain selection is the most important factor for determining health effects. Further studies may consider gut microbiota as a novel target for prevention and management of MetS components and other cardiovascular risks.

Utility of the American-European Consensus Group and American College of Rheumatology Classification Criteria for Sjögren's syndrome in patients with systemic autoimmune diseases in the clinical setting.

PubMed

Hernández-Molina, Gabriela; Avila-Casado, Carmen; Nuñez-Alvarez, Carlos; Cárdenas-Velázquez, Francisco; Hernández-Hernández, Carlos; Luisa Calderillo, María; Marroquín, Verónica; Recillas-Gispert, Claudia; Romero-Díaz, Juanita; Sánchez-Guerrero, Jorge

2015-03-01

The aim of this study was to evaluate the feasibility and performance of the American-European Consensus Group (AECG) and ACR Classification Criteria for SS in patients with systemic autoimmune diseases. Three hundred and fifty patients with primary SS, SLE, RA or scleroderma were randomly selected from our patient registry. Each patient was clinically diagnosed as probable/definitive SS or non-SS following a standardized evaluation including clinical symptoms and manifestations, confirmatory tests, fluorescein staining test, autoantibodies, lip biopsy and medical chart review. Using the clinical diagnosis as the gold standard, the degree of agreement with each criteria set and between the criteria sets was estimated. One hundred fifty-four (44%) patients were diagnosed with SS. The AECG criteria were incomplete in 36 patients (10.3%) and the ACR criteria in 96 (27.4%; P < 0.001). Nevertheless, their ability to classify patients was almost identical, with a sensitivity of 61.6 vs 62.3 and a specificity of 94.3 vs 91.3, respectively. Either set of criteria was met by 123 patients (80%); 95 (61.7%) met the AECG criteria and 96 (62.3%) met the ACR criteria, but only 68 (44.2%) patients met both sets. The concordance rate between clinical diagnosis and AECG or ACR criteria was moderate (k statistic 0.58 and 0.55, respectively). Among 99 patients with definitive SS sensitivity was 83.3 vs 77.7 and specificity was 90.8 vs 85.6, respectively. A discrepancy between clinical diagnosis and criteria was seen in 59 patients (17%). The feasibility of the SS AECG criteria is superior to that of the ACR criteria, however, their performance was similar among patients with systemic autoimmune diseases. A subset of SS patients is still missed by both criteria sets. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Met receptor tyrosine kinase signals through a cortactin–Gab1 scaffold complex, to mediate invadopodia

PubMed Central

Rajadurai, Charles V.; Havrylov, Serhiy; Zaoui, Kossay; Vaillancourt, Richard; Stuible, Matthew; Naujokas, Monica; Zuo, Dongmei; Tremblay, Michel L.; Park, Morag

2012-01-01

Summary Invasive carcinoma cells form actin-rich matrix-degrading protrusions called invadopodia. These structures resemble podosomes produced by some normal cells and play a crucial role in extracellular matrix remodeling. In cancer, formation of invadopodia is strongly associated with invasive potential. Although deregulated signals from the receptor tyrosine kinase Met (also known as hepatocyte growth factor are linked to cancer metastasis and poor prognosis, its role in invadopodia formation is not known. Here we show that stimulation of breast cancer cells with the ligand for Met, hepatocyte growth factor, promotes invadopodia formation, and in aggressive gastric tumor cells where Met is amplified, invadopodia formation is dependent on Met activity. Using both GRB2-associated-binding protein 1 (Gab1)-null fibroblasts and specific knockdown of Gab1 in tumor cells we show that Met-mediated invadopodia formation and cell invasion requires the scaffold protein Gab1. By a structure–function approach, we demonstrate that two proline-rich motifs (P4/5) within Gab1 are essential for invadopodia formation. We identify the actin regulatory protein, cortactin, as a direct interaction partner for Gab1 and show that a Gab1–cortactin interaction is dependent on the SH3 domain of cortactin and the integrity of the P4/5 region of Gab1. Both cortactin and Gab1 localize to invadopodia rosettes in Met-transformed cells and the specific uncoupling of cortactin from Gab1 abrogates invadopodia biogenesis and cell invasion downstream from the Met receptor tyrosine kinase. Met localizes to invadopodia along with cortactin and promotes phosphorylation of cortactin. These findings provide insights into the molecular mechanisms of invadopodia formation and identify Gab1 as a scaffold protein involved in this process. PMID:22366451

Activated HGF-c-Met Axis in Head and Neck Cancer

PubMed Central

Arnold, Levi; Enders, Jonathan; Thomas, Sufi Mary

2017-01-01

Head and neck squamous cell carcinoma (HNSCC) is a highly morbid disease. Recent developments including Food and Drug Administration (FDA) approved molecular targeted agent’s pembrolizumab and cetuximab show promise but did not improve the five-year survival which is currently less than 40%. The hepatocyte growth factor receptor; also known as mesenchymal–epithelial transition factor (c-Met) and its ligand hepatocyte growth factor (HGF) are overexpressed in head and neck squamous cell carcinoma (HNSCC); and regulates tumor progression and response to therapy. The c-Met pathway has been shown to regulate many cellular processes such as cell proliferation, invasion, and angiogenesis. The c-Met pathway is involved in cross-talk, activation, and perpetuation of other signaling pathways, curbing the cogency of a blockade molecule on a single pathway. The receptor and its ligand act on several downstream effectors including phospholipase C gamma (PLCγ), cellular Src kinase (c-Src), phosphotidylinsitol-3-OH kinase (PI3K) alpha serine/threonine-protein kinase (Akt), mitogen activate protein kinase (MAPK), and wingless-related integration site (Wnt) pathways. They are also known to cross-talk with other receptors; namely epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) and specifically contribute to treatment resistance. Clinical trials targeting the c-Met axis in HNSCC have been undertaken because of significant preclinical work demonstrating a relationship between HGF/c-Met signaling and cancer cell survival. Here we focus on HGF/c-Met impact on cellular signaling in HNSCC to potentiate tumor growth and disrupt therapeutic efficacy. Herein we summarize the current understanding of HGF/c-Met signaling and its effects on HNSCC. The intertwining of c-Met signaling with other signaling pathways provides opportunities for more robust and specific therapies, leading to better clinical outcomes. PMID:29231907

Is the Veterans Specific Activity Questionnaire Valid to Assess Older Adults Aerobic Fitness?

PubMed

de Carvalho Bastone, Alessandra; de Souza Moreira, Bruno; Teixeira, Claudine Patrícia; Dias, João Marcos Domingues; Dias, Rosângela Corrêa

2016-01-01

Aerobic fitness in older adults is related to health status, incident disability, nursing home admission, and all-cause mortality. The most accurate quantification of aerobic fitness, expressed as peak oxygen consumption in mL·kg·min, is the cardiorespiratory exercise test; however, it is not feasible in all settings and might offer risk to patients. The Veterans Specific Activity Questionnaire (VSAQ) is a 13-item self-administered symptom questionnaire that estimates aerobic fitness expressed in metabolic equivalents (METs) and has been validated to cardiovascular patients. The purpose of this study was to assess the validity and reliability of the VSAQ in older adults without specific health conditions. A methodological study with a cross-sectional design was conducted with 28 older adults (66-86 years). The VSAQ was administered on 3 occasions by 2 evaluators. Aerobic capacity in METs as measured by the VSAQ was compared with the METs found in an incremental shuttle walk test (ISWT) performed with a portable metabolic measurement system and with accelerometer data. The validity of the VSAQ was found to be moderate-to-good when compared with the METs and distance measured by the ISWT and with the moderate activity per day and steps per day obtained by accelerometry. The Bland-Altman graph analysis showed no values outside the limits of agreement, suggesting good precision between the METs estimated by questionnaire and the METs measured by the ISWT. Also, the intrarater and interrater reliabilities of the instrument were good. The results showed that the VSAQ is a valuable tool to assess the aerobic fitness of older adults.

Meeting stroke survivors' perceived needs: a qualitative study of a community-based exercise and education scheme.

PubMed

Reed, Mary; Harrington, Rachel; Duggan, Aine; Wood, Victorine A

2010-01-01

A qualitative study using a phenomenological approach, to explore stroke survivors' needs and their perceptions of whether a community stroke scheme met these needs. Semi-structured in-depth interviews of 12 stroke survivors, purposively selected from participants attending a new community stroke scheme. Interpretative phenomenological analysis of interviews by two researchers independently. Participants attending the community stroke scheme sought to reconstruct their lives in the aftermath of their stroke. To enable this they needed internal resources of confidence and sense of purpose to 'create their social self', and external resources of 'responsive services' and an 'informal support network', to provide direction and encouragement. Participants felt the community stroke scheme met some of these needs through exercise, goal setting and peer group interaction, which included social support and knowledge acquisition. Stroke survivors need a variety of internal and external resources so that they can rebuild their lives positively post stroke. A stroke-specific community scheme, based on exercise, life-centred goal setting, peer support and knowledge acquisition, is an external resource that can help with meeting some of the stroke survivor's needs.

Cloud Type Classification (cldtype) Value-Added Product

DOE Office of Scientific and Technical Information (OSTI.GOV)

Flynn, Donna; Shi, Yan; Lim, K-S

The Cloud Type (cldtype) value-added product (VAP) provides an automated cloud type classification based on macrophysical quantities derived from vertically pointing lidar and radar. Up to 10 layers of clouds are classified into seven cloud types based on predetermined and site-specific thresholds of cloud top, base and thickness. Examples of thresholds for selected U.S. Department of Energy (DOE) Atmospheric Radiation Measurement (ARM) Climate Research Facility sites are provided in Tables 1 and 2. Inputs for the cldtype VAP include lidar and radar cloud boundaries obtained from the Active Remotely Sensed Cloud Location (ARSCL) and Surface Meteorological Systems (MET) data. Rainmore » rates from MET are used to determine when radar signal attenuation precludes accurate cloud detection. Temporal resolution and vertical resolution for cldtype are 1 minute and 30 m respectively and match the resolution of ARSCL. The cldtype classification is an initial step for further categorization of clouds. It was developed for use by the Shallow Cumulus VAP to identify potential periods of interest to the LASSO model and is intended to find clouds of interest for a variety of users.« less

Model specification and bootstrapping for multiply imputed data: An application to count models for the frequency of alcohol use

PubMed Central

Comulada, W. Scott

2015-01-01

Stata’s mi commands provide powerful tools to conduct multiple imputation in the presence of ignorable missing data. In this article, I present Stata code to extend the capabilities of the mi commands to address two areas of statistical inference where results are not easily aggregated across imputed datasets. First, mi commands are restricted to covariate selection. I show how to address model fit to correctly specify a model. Second, the mi commands readily aggregate model-based standard errors. I show how standard errors can be bootstrapped for situations where model assumptions may not be met. I illustrate model specification and bootstrapping on frequency counts for the number of times that alcohol was consumed in data with missing observations from a behavioral intervention. PMID:26973439

Prevalence of metabolic syndrome and its related factors among North Korean refugees in South Korea: a cross-sectional study

PubMed Central

Kim, Yoon Jung; Lee, Yo Han; Lee, Yun Jeong; Kim, Kyeong Jin; An, Jee Hyun; Kim, Nam Hoon; Kim, Hee Young; Choi, Dong Seop; Kim, Sin Gon

2016-01-01

Objectives To determine the prevalence of metabolic syndrome (MetS) and its related factors among North Korean refugees (NKR) in South Korea. Design Cross-sectional study conducted using a questionnaire and anthropometric and biochemical data on NKR in South Korea. Setting Seoul, South Korea. Participants A sample of NKR who voluntarily underwent medical examinations in Anam Hospital of Korea University, Seoul, South Korea (N=708, consisting of 161 males and 547 females). To compare the prevalence of MetS, 1416 age- and gender-matched individuals from the South Korean population (SKP, at a ratio of 1:2 to NKR) were randomly selected from the fifth Korean National Health and Nutrition Examination Survey. Main outcome measures The prevalence of MetS and its related factors among NKR in South Korea and comparison with its prevalence among the general SKP. Results The prevalence of MetS among male and female NKR in South Korea was 19.7% and 17.2%, respectively. Although obesity is more prevalent in South than in North Korea, we found no difference in the prevalence of MetS between the female NKR and SKP groups (17.2% vs 16.6%, respectively; p=0.830). As regards the males, the small sample size of the NKR group yielded insufficient evidence of any difference in MetS prevalence between the NKR and SKP groups (19.7% vs 26.2%, respectively; p=0.134). We found that excess weight gain (≥5%) in South Korea was significantly associated with MetS among NKR. Conclusions The prevalence of MetS among NKR did not differ from that in the SKP group despite the lower prevalence of obesity in NKR than in the general SKP. The fact that excess weight gain in South Korea was associated with the risk of MetS suggests that public health policy makers should focus on preventing excess weight gain in NKR during resettlement in South Korea. PMID:27251685

The effect of ziprasidone on metabolic syndrome risk factors in subjects with schizophrenia: a 1 year, open-label, prospective study.

PubMed

Chue, Pierre; Mandel, Francine S; Therrien, François

2014-06-01

Metabolic syndrome (MetS) is prevalent in subjects with schizophrenia-related psychotic disorders and contributes to increased rates of premature death due to cardiovascular disease. This study examined the impact of switching from another antipsychotic to ziprasidone on the distribution of the number of risk factors for MetS in subjects with schizophrenia or related psychotic disorders. In this 1 year, open-label, prospective study, all subjects received ziprasidone 40-160 mg/day. Standard exclusion criteria included treatment resistance, physical health disorders, and substance abuse. The primary end point was the percentage of subjects achieving a reduction from baseline of at least one risk factor for MetS at end point (week 52 or premature discontinuation) in the per-protocol population (treated for at least 16 weeks). Secondary end points included the mean change from baseline in number of MetS risk factors, the prevalence of MetS, individual MetS risk factors (waist circumference, blood pressure, fasting triglycerides, high-density lipoprotein cholesterol, and glucose), and 10 year coronary heart disease (Framingham score) risk. www.clinicaltrials.gov: NCT00748566. Of 114 evaluable subjects, 58.77% demonstrated one less MetS risk factor at week 52 (last observation carried forward) compared with baseline. Secondary end points also improved, with reductions in other metabolic parameters (fasting low-density lipoprotein cholesterol, total cholesterol and serum insulin, weight, body mass index and glycosylated hemoglobin [HbA1c]). The 10 year coronary heart disease risk decreased continually over time. The open-label and uncontrolled design is a limitation of the study. Ziprasidone treatment reduced both the rate of MetS and its individual risk factors in subjects with schizophrenia and related psychotic disorders. The results have implications for the selection of first-line treatments in schizophrenia and related psychotic disorders, and provide treatment options for subjects who have developed MetS as a result of other antipsychotics.

Serum Antioxidant Concentrations and Metabolic Syndrome Are Associated among U.S. Adolescents in Recent National Surveys123

PubMed Central

Beydoun, May A.; Canas, J. Atilio; Beydoun, Hind A.; Chen, Xiaoli; Shroff, Monal R.; Zonderman, Alan B.

2012-01-01

Specific micronutrients, including retinol, retinyl esters, carotenoids [α-carotene, β-carotene (cis+trans), β-cryptoxanthin, lutein+zeaxanthin, and total lycopene], vitamin E, and vitamin C have antiinflammatory and antioxidant effects, properties shown to reduce oxidative stress, a process that accompanies the pathogenesis of many chronic diseases. It is still largely unknown whether they are associated with the occurrence of metabolic syndrome (MetS) in the adolescent U.S. population. MetS was defined by the International Diabetes Federation (IDF) criteria. Other non-MetS outcomes relying on blood measurements were elevated HOMA-IR, C-reactive protein (CRP), and hyperuricemia. We tested associations between serum antioxidants and MetS outcomes among adolescents aged 12–19 y using cross-sectional data from NHANES 2001–2006 (n = 782–4285). IDF MetS prevalence was estimated at 7% among boys and 3% among girls. In adjusted models, adolescents with MetS had consistently lower carotenoid concentrations compared with their counterparts without MetS. Total carotenoids were also inversely related to HOMA-IR and CRP. Vitamin C was inversely related to uric acid level and MetS binary outcome. Retinol+retinyl esters exhibited an inverse relationship with CRP and a positive relationship with uric acid and HOMA-IR as well as MetS binary outcome. Vitamin E had no association with MetS, particularly after controlling for serum cholesterol and TG. In conclusion, among U.S. adolescents, serum carotenoid concentrations were inversely associated with MetS status, HOMA-IR, and CRP, whereas serum vitamin C was inversely related to MetS status and serum uric acid. Vitamin E had no consistent association with MetS, whereas retinol+retinyl esters had a positive relationship with HOMA-IR, uric acid, and MetS, while being inversely related to CRP. These associations need further study. PMID:22810988

Skinfold reference curves and their use in predicting metabolic syndrome risk in children.

PubMed

Andaki, Alynne C R; Quadros, Teresa M B de; Gordia, Alex P; Mota, Jorge; Tinôco, Adelson L A; Mendes, Edmar L

To draw skinfold (SF) reference curves (subscapular, suprailiac, biceps, triceps) and to determine SF cutoff points for predicting the risk of metabolic syndrome (MetS) in children aged 6-10 years old. This was a cross-sectional study with a random sample of 1480 children aged 6-10 years old, 52.2% females, from public and private schools located in the urban and rural areas of the municipality of Uberaba (MG). Anthropometry, blood pressure, and fasting blood samples were taken at school, following specific protocols. The LMS method was used to draw the reference curves and ROC curve analysis to determine the accuracy and cutoff points for the evaluated skinfolds. The four SF evaluated (subscapular, suprailiac, biceps, and triceps) and their sum (∑4SF) were accurate in predicting MetS for both girls and boys. Additionally, cutoffs have been proposed and percentile curves (p5, p10, p25, p50, p75, p90, and p95) were outlined for the four SF and ∑4SF, for both genders. SF measurements were accurate in predicting metabolic syndrome in children aged 6-10 years old. Age- and gender-specific smoothed percentiles curves of SF provide a reference for the detection of risk for MetS in children. Copyright © 2017. Published by Elsevier Editora Ltda.

Psychiatric disorders in youth in juvenile detention.

PubMed

Teplin, Linda A; Abram, Karen M; McClelland, Gary M; Dulcan, Mina K; Mericle, Amy A

2002-12-01

Given the growth of juvenile detainee populations, epidemiologic data on their psychiatric disorders are increasingly important. Yet, there are few empirical studies. Until we have better epidemiologic data, we cannot know how best to use the system's scarce mental health resources. Using the Diagnostic Interview Schedule for Children version 2.3, interviewers assessed a randomly selected, stratified sample of 1829 African American, non-Hispanic white, and Hispanic youth (1172 males, 657 females, ages 10-18 years) who were arrested and detained in Cook County, Illinois (which includes Chicago and surrounding suburbs). We present 6-month prevalence estimates by demographic subgroups (sex, race/ethnicity, and age) for the following disorders: affective disorders (major depressive episode, dysthymia, manic episode), anxiety (panic, separation anxiety, overanxious, generalized anxiety, and obsessive-compulsive disorders), psychosis, attention-deficit/hyperactivity disorder, disruptive behavior disorders (oppositional defiant disorder, conduct disorder), and substance use disorders (alcohol and other drugs). Nearly two thirds of males and nearly three quarters of females met diagnostic criteria for one or more psychiatric disorders. Excluding conduct disorder (common among detained youth), nearly 60% of males and more than two thirds of females met diagnostic criteria and had diagnosis-specific impairment for one or more psychiatric disorders. Half of males and almost half of females had a substance use disorder, and more than 40% of males and females met criteria for disruptive behavior disorders. Affective disorders were also prevalent, especially among females; more than 20% of females met criteria for a major depressive episode. Rates of many disorders were higher among females, non-Hispanic whites, and older adolescents. These results suggest substantial psychiatric morbidity among juvenile detainees. Youth with psychiatric disorders pose a challenge for the juvenile justice system and, after their release, for the larger mental health system.

The Prediction of Drug-Disease Correlation Based on Gene Expression Data.

PubMed

Cui, Hui; Zhang, Menghuan; Yang, Qingmin; Li, Xiangyi; Liebman, Michael; Yu, Ying; Xie, Lu

2018-01-01

The explosive growth of high-throughput experimental methods and resulting data yields both opportunity and challenge for selecting the correct drug to treat both a specific patient and their individual disease. Ideally, it would be useful and efficient if computational approaches could be applied to help achieve optimal drug-patient-disease matching but current efforts have met with limited success. Current approaches have primarily utilized the measureable effect of a specific drug on target tissue or cell lines to identify the potential biological effect of such treatment. While these efforts have met with some level of success, there exists much opportunity for improvement. This specifically follows the observation that, for many diseases in light of actual patient response, there is increasing need for treatment with combinations of drugs rather than single drug therapies. Only a few previous studies have yielded computational approaches for predicting the synergy of drug combinations by analyzing high-throughput molecular datasets. However, these computational approaches focused on the characteristics of the drug itself, without fully accounting for disease factors. Here, we propose an algorithm to specifically predict synergistic effects of drug combinations on various diseases, by integrating the data characteristics of disease-related gene expression profiles with drug-treated gene expression profiles. We have demonstrated utility through its application to transcriptome data, including microarray and RNASeq data, and the drug-disease prediction results were validated using existing publications and drug databases. It is also applicable to other quantitative profiling data such as proteomics data. We also provide an interactive web interface to allow our Prediction of Drug-Disease method to be readily applied to user data. While our studies represent a preliminary exploration of this critical problem, we believe that the algorithm can provide the basis for further refinement towards addressing a large clinical need.

Secular Trend of Metabolic Syndrome and Its Components in a Cohort of Iranian Adults from 2001 to 2013.

PubMed

Khosravi-Boroujeni, Hossein; Sarrafzadegan, Nizal; Sadeghi, Masoumeh; Roohafza, Hamidreza; Talaei, Mohammad; Ng, Shu-Kay; Phung, Hai; Pourmogaddas, Ali; Ahmed, Faruk

2017-04-01

Metabolic syndrome (MetS) and its components increase the risk of developing cardiovascular diseases, type 2 diabetes, and all-cause mortality. Reports on the trends of MetS and its components in longitudinal studies are scarce, especially in low- and middle-income countries. This study was designed to investigate the prevalence and trends of MetS and its components in a cohort of Iranian adults from 2001 to 2013. Participants were followed up for 12 years in a longitudinal population-based study of 6500 adults aged 35 years and older in 2001. Participants were randomly selected from three provinces in central Iran. Sociodemographic characteristics, anthropometry, blood pressure, and various biochemical indices were collected in 2001, 2007, and 2013. Secular trend and age-adjusted trend of MetS and its components were calculated from 2001 to 2013. The standardized prevalence of MetS, hypertension, low high-density lipoprotein cholesterol (HDL-C), abdominal obesity, and diabetes/impaired glucose tolerance (IGT) increased over the 12 years (6.9%, 5.5%, 12.0%, 2.3%, and 18.7%, respectively), while the prevalence of hypertriglyceridemia decreased by 15.5% during this period. The prevalence of MetS, low HDL-C, and abdominal obesity were higher in females than males in all three phases. Moreover, the increases in the prevalence of these metabolic abnormalities were higher in the rural population than in the urban population. The present study underscored the increasing trends in MetS and most of its risk factors, thus, to prevent an increase in the cardiovascular risk factors, there is a need to improve lifestyle by education, screening, and treatment of abnormalities.

PREVALENCE OF METABOLIC SYNDROME AMONG ADOLESCENTS IN A CITY IN THE MEDITERRANEAN AREA: COMPARISON OF TWO DEFINITIONS.

PubMed

Galera-Martínez, Rafael; García-García, Emilio; Vázquez-López, M Ángeles; Ortiz-Pérez, María; Ruiz-Sánchez, Ana Mar; Martín-González, Manuel; Garrido-Fernández, Pablo; Bonillo-Perales, Antonio

2015-08-01

there are few studies on the prevalence of metabolic syndrome (MetS) in European adolescent populations, and some have reported a higher prevalence in the Mediterranean basin area. Our objective was to examine the prevalence of MetS in adolescents in a Mediterranean city of Spain, comparing two different definitions of MetS and the associated risk factors. a cross-sectional population-based study was conducted among 379 adolescents aged 12-16.9 years, selected using a random sampling method. Anthropometric measurements and fasting blood samples were obtained. The definitions of MetS used were that of the National Cholesterol Education Program's Adult Treatment Panel III (NCEP-ATPIII) and that of the International Diabetes Federation (IDF). Kappa coefficient was used to measure the agreement between definitions and a multivariate logistic regression model to determine the associated risk factors. the prevalence of MetS was 5.7% (95%CI 3.33-8.07) according to the NCEP-ATPIII definition and 3.8% (95%CI 1.85-5.75) according to the IDF definition. No differences between the sexes or by age groups were found. The agreement between the two definitions was very good (kappa 0.815), especially in the obese subsample, but was lower in normal weight adolescents (kappa 0.497). Insulin resistance and obesity were associated with both definitions. the prevalence of MetS in our adolescent population is higher than the European media. Although the overall agreement between both definitions was very good, the prevalence was higher using the NCEP-ATPIII criteria. Independently of the definition used, obesity and insulin resistance were risk factors for MetS. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

An exploration of medical emergency team intervention at the end of life for people with advanced cancer.

PubMed

Brown, Christine; Drosdowsky, Allison; Krishnasamy, Meinir

2017-12-01

Recent advances in cancer therapies offer survival benefit when cure is no longer possible. The contribution of the Medical Emergency Teams (METs) in the context of advancing disease has received little empirical consideration. This study set out to explore MET intervention at the end of life for people with advanced cancer in an Australian comprehensive cancer centre, and its impact on quality of death. A retrospective medical chart review was undertaken to explore MET response for people with advanced (incurable) cancer nearing end of life. Occurrence of MET interventions at the end of life and a quality of death score were recorded for two randomly selected cohorts of patients, those who experienced a MET response within their last week of life (n = 50) and those who did not (n = 50). The cohort who did not receive MET intervention had a significantly higher (better) quality of death score when compared with patients who did receive a MET intervention (p = 0.01). Within the cohort who received a MET intervention, a subgroup (n = 19) where the MET influenced end-of-life decision-making had a significantly higher quality of death score (p = 0.02) than patients in the MET cohort (n = 31) where the MET did not influence end-of-life care. The contribution of the MET to end-of-life care for patients with cancer has not previously been reported. Further research is now needed to prospectively examine MET involvement at the end of life with consideration to quality of patient care and death, family experience, and support requirements of MET members. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mediterranean diet and metabolic syndrome in an urban population: the Athens Study.

PubMed

Gouveri, Evanthia T; Tzavara, Chara; Drakopanagiotakis, Fotios; Tsaoussoglou, Marina; Marakomichelakis, Georgios E; Tountas, Yannis; Diamantopoulos, Emmanuel J

2011-10-01

Previous studies demonstrated the beneficial impact of the Mediterranean diet (MedDiet) on metabolic syndrome (MetS). The aim of this study was to retrospectively investigate the association between MedDiet and MetS in a representative sample of the Athenian population in the early 1980s, when MetS had not been established as an entity yet. In a cross-sectional epidemiologic survey of cardiovascular disease (CVD), 2,074 randomly selected adults were examined: 900 men and 1,174 women (age, 46.9 ± 14.9 years). MetS was defined according to criteria of the National Cholesterol Education Program-Adult Treatment Panel III. A validated questionnaire concerning nutrition habits was administered, and MedDiet was assessed according to guidelines of the Division of Nutrition/Epidemiology, Athens University Medical School. Overall, 1,023 participants (49.3%) followed MedDiet (47.3% men, 52.0% women, P = .033) with similar rates across age groups (P = .337). MetS was diagnosed in 24.0% of those following MedDiet, compared with 27.9% of those not following it (P = .041). Participants with CVD or diabetes mellitus were less likely to follow MedDiet (43% vs 50%, P = .009). Multivariate analysis revealed that MedDiet is associated with a 20% reduction in MetS (odds ratio = 0.80, 95% confidence interval = 0.65-0.98), after adjustment for age, gender, smoking, light physical activity, serum levels of low-density lipoprotein cholesterol and γ-glutamyl transferase, diabetes mellitus, CVD, family history of hypertension, and/or hyperlipidemia. Results indicate that adherence to MedDiet may attenuate the prevalence of MetS and, consequently, the increasing burden of diabetes mellitus and CVD, especially in urban populations.

Prostatic Response to Supranutritional Selenium Supplementation: Comparison of the Target Tissue Potency of Selenomethionine vs. Selenium-Yeast on Markers of Prostatic Homeostasis

PubMed Central

Waters, David J.; Shen, Shuren; Kengeri, Seema S.; Chiang, Emily C.; Combs, Gerald F.; Morris, J. Steven; Bostwick, David G.

2012-01-01

Prostate cancer is the product of dysregulated homeostasis within the aging prostate. Supplementation with selenium in the form of selenized yeast (Se-yeast) significantly reduced prostate cancer incidence in the Nutritional Prevention of Cancer Trial. Conversely, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed no such cancer-protective advantage using selenomethionine (SeMet). The possibility that SeMet and Se-yeast are not equipotent in promoting homeostasis and cancer risk reduction in the aging prostate has not been adequately investigated; no direct comparison has ever been reported in man or animals. Here, we analyzed data on prostatic responses to SeMet or Se-yeast from a controlled feeding trial of 49 elderly beagle dogs—the only non-human species to frequently develop prostate cancer during aging—randomized to one of five groups: control; low-dose SeMet, low-dose Se-yeast (3 μg/kg); high-dose SeMet, high-dose Se-yeast (6 μg/kg). After seven months of supplementation, we found no significant selenium form-dependent differences in toenail or intraprostatic selenium concentration. Next, we determined whether SeMet or Se-yeast acts with different potency on six markers of prostatic homeostasis that likely contribute to prostate cancer risk reduction—intraprostatic dihydrotestosterone (DHT), testosterone (T), DHT:T, and epithelial cell DNA damage, proliferation, and apoptosis. By analyzing dogs supplemented with SeMet or Se-yeast that achieved equivalent intraprostatic selenium concentration after supplementation, we showed no significant differences in potency of either selenium form on any of the six parameters over three different ranges of target tissue selenium concentration. Our findings, which represent the first direct comparison of SeMet and Se-yeast on a suite of readouts in the aging prostate that reflect flux through multiple gene networks, do not further support the notion that the null results of SELECT are attributable to differences in prostatic consequences achievable through daily supplementation with SeMet, rather than Se-yeast. PMID:23201838

Gender Differences in Lifestyle Factors Associated with Metabolic Syndrome and Preliminary Metabolic Syndrome in the General Population: The Watari Study

PubMed Central

Hattori, Tomomi; Konno, Satoshi; Munakata, Masanori

2017-01-01

Objective In Japan, metabolic syndrome (MetS) and preliminary metabolic syndrome (preMetS) are more prevalent in men; however, it remains unclear whether the relationship between these metabolic disorders and lifestyle factors is similar between genders. Methods We examined waist circumference, blood pressure, fasting blood, and various lifestyle factors in 3,166 individuals aged from 30-79 years of age from the Japanese general population. MetS was diagnosed on the basis of central obesity - assessed by waist circumference - plus two or more of the following cardio-metabolic risks according to Japanese criteria: high blood pressure, hyperglycemia, and lipid abnormality. Central obesity plus one of the risks was defined as preMetS. Results Men had a significantly higher prevalence of MetS (23.3% vs. 8.7%, p<0.001) and preMetS (21.2% vs. 10.2%, p<0.001) than women. An age-adjusted logistic regression analysis revealed that heavy drinkers were associated with an increased probability of MetS (odds ratio, 1.91: 95% confidence interval, 1.29-2.83) and preMetS (1.69: 1.11-2.58); fast eaters were also related to preMetS (1.83: 1.33-2.55) and MetS (1.55: 1.12-2.15) in men. Lacking regular exercise was significantly associated with preMetS (1.38: 1.03-1.85), but not MetS. In women, preMetS was significantly associated with fast eaters and lacking regular exercise (1.44: 1.01-2.07 and 1.41: 1.02-1.96, respectively); a stepwise increase in each odds ratio (2.02: 1.40-2.91 and 1.47: 1.03-2.09, respectively) was also observed for MetS. Conclusion The relationships between lifestyle factors and MetS or preMetS differed between men and women, which suggests the need for gender-specific lifestyle modification to effectively prevent MetS. PMID:28794374

Prevalence of metabolic syndrome and its association with lower urinary tract symptoms and sexual function.

PubMed

Plata, M; Caicedo, J I; Trujillo, C G; Mariño-Alvarez, Á M; Fernandez, N; Gutierrez, A; Godoy, F; Cabrera, M; Cataño-Cataño, J G; Robledo, D

2017-10-01

To estimate the frequency of metabolic syndrome (MetS) in a daily urology practice and to determine its association with lower urinary tract symptoms (LUTS) and erectile dysfunction (ED). A retrospective study was conducted. Data from all male patients aged ≥40 years who attended our outpatient urology clinic from 2010 to 2011 was collected. Prevalence of MetS was determined, and LUTS and ED were assessed. A logistic model was used to determine possible associations, controlling for confounders and interaction factors. A total of 616 patients were included. MetS was observed in 43.8% (95% CI 39.6-48.3). The bivariate model showed an association between MetS and LUTS (p<0.01), but not between MetS and ED. The logistic model showed an association between MetS and the International Prostate Symptom Score (IPSS), while controlling for other variables. Patients exhibiting moderate LUTS had a greater risk for MetS than patients with mild LUTS (OR 1.83, 95% CI 1.14-2.94). After analyzing for individual components of MetS, positive associations were found between diabetes and severe LUTS (OR 1.3, 95% CI 1.24-7.1), and between diabetes and ED (OR 2.57, 95% CI 1.12-5.8). This study was able to confirm an association between MetS and LUTS, but not for ED. Specific components such as diabetes were associated to both. Geographical differences previously reported in the literature might account for these findings. Given that MetS is frequent among urological patients, it is advisable that urologists actively screen for it. Copyright © 2017 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

AtaT blocks translation initiation by N-acetylation of the initiator tRNAfMet.

PubMed

Jurėnas, Dukas; Chatterjee, Sneha; Konijnenberg, Albert; Sobott, Frank; Droogmans, Louis; Garcia-Pino, Abel; Van Melderen, Laurence

2017-06-01

Toxin-antitoxin (TA) loci are prevalent in bacterial genomes. They are suggested to play a central role in dormancy and persister states. Under normal growth conditions, TA toxins are neutralized by their cognate antitoxins, and under stress conditions, toxins are freed and inhibit essential cellular processes using a variety of mechanisms. Here we characterize ataR-ataT, a novel TA system, from enterohemorrhagic Escherichia coli. We show that the toxin AtaT is a GNAT family enzyme that transfers an acetyl group from acetyl coenzyme A to the amine group of the methionyl aminoacyl moiety of initiator tRNA. AtaT specifically modifies Met-tRNA fMet , but no other aminoacyl-tRNAs, including the elongator Met-tRNA Met . We demonstrate that once acetylated, AcMet-tRNA fMet fails to interact with initiation factor-2 (IF2), resulting in disruption of the translation initiation complex. This work reveals a new mechanism of translation inhibition and confirms Met-tRNA fMet as a prime target to efficiently block cell growth.

Advanced Thermally Stable Coal-Based Jet Fuels

DTIC Science & Technology

2008-02-01

of hydrotreated refined chemical oil derived jet fuels in the pyrolytic regime. Preprints of Papers-American Chemical Society Division of Fuel...hydrogenation of a mixture of light cycle oil and refined chemical oil met or exceeded all but four JP-8 specifications. The fuel has excellent low-temperature...mixture of light cycle oil and refined chemical oil met or exceeded all but four JP-8 specifications. The fuel has excellent low-temperature viscosity

Targeted High Performance Liquid Chromatography Tandem Mass Spectrometry-based Metabolomics differentiates metabolic syndrome from obesity.

PubMed

Zhong, Fanyi; Xu, Mengyang; Bruno, Richard S; Ballard, Kevin D; Zhu, Jiangjiang

2017-04-01

Both obesity and the metabolic syndrome are risk factors for type 2 diabetes and cardiovascular disease. Identification of novel biomarkers are needed to distinguish metabolic syndrome from equally obese individuals in order to direct them to early interventions that reduce their risk of developing further health problems. We utilized mass spectrometry-based targeted metabolic profiling of 221 metabolites to evaluate the associations between metabolite profiles and established metabolic syndrome criteria (i.e. elevated waist circumference, hypertension, elevated fasting glucose, elevated triglycerides, and low high-density lipoprotein cholesterol) in plasma samples from obese men ( n = 29; BMI = 35.5 ± 5.2 kg/m 2 ) and women ( n = 40; 34.9 ± 6.7 kg/m 2 ), of which 26 met the criteria for metabolic syndrome (17 men and 9 women). Compared to obese individuals without metabolic syndrome, univariate statistical analysis and partial least squares discriminant analysis showed that a specific group of metabolites from multiple metabolic pathways (i.e. purine metabolism, valine, leucine and isoleucine degradation, and tryptophan metabolism) were associated with the presence of metabolic syndrome. Receiver operating characteristic curves generated based on the PLS-DA models showed excellent areas under the curve (0.85 and 0.96, for metabolites only model and enhanced metabolites model, respectively), high specificities (0.86 and 0.93), and good sensitivities (0.71 and 0.91). Moreover, principal component analysis revealed that metabolic profiles can be used to further differentiate metabolic syndrome with 3 versus 4-5 metabolic syndrome criteria. Collectively, these findings support targeted metabolomics approaches to distinguish metabolic syndrome from obesity alone, and to stratify metabolic syndrome status based on the number of criteria met. Impact statement We utilized mass spectrometry-based targeted metabolic profiling of 221 metabolites to evaluate the associations between metabolite profiles and established MetS criteria. To our best knowledge, the findings of this study provide the first evidence that metabolic profiles can be used to differentiate participants with MetS from similarly obese individuals who do not meet established criteria of MetS. Furthermore, the study demonstrated that within MetS participants, their unique metabolic profiles correlated to the number of criteria used for MetS determination. Taken together, this metabolic profiling approach can potentially serve as a novel tool for MetS detection and monitoring, and provide useful metabolic information for future interventions targeting obesity and MetS.

Environment-specific noise suppression for improved speech intelligibility by cochlear implant users.

PubMed

Hu, Yi; Loizou, Philipos C

2010-06-01

Attempts to develop noise-suppression algorithms that can significantly improve speech intelligibility in noise by cochlear implant (CI) users have met with limited success. This is partly because algorithms were sought that would work equally well in all listening situations. Accomplishing this has been quite challenging given the variability in the temporal/spectral characteristics of real-world maskers. A different approach is taken in the present study focused on the development of environment-specific noise suppression algorithms. The proposed algorithm selects a subset of the envelope amplitudes for stimulation based on the signal-to-noise ratio (SNR) of each channel. Binary classifiers, trained using data collected from a particular noisy environment, are first used to classify the mixture envelopes of each channel as either target-dominated (SNR>or=0 dB) or masker-dominated (SNR<0 dB). Only target-dominated channels are subsequently selected for stimulation. Results with CI listeners indicated substantial improvements (by nearly 44 percentage points at 5 dB SNR) in intelligibility with the proposed algorithm when tested with sentences embedded in three real-world maskers. The present study demonstrated that the environment-specific approach to noise reduction has the potential to restore speech intelligibility in noise to a level near to that attained in quiet.

Ethnic disparities in the prevalence of metabolic syndrome and its risk factors in the Suriname Health Study: a cross-sectional population study.

PubMed

Krishnadath, Ingrid S K; Toelsie, Jerry R; Hofman, Albert; Jaddoe, Vincent W V

2016-12-07

The metabolic syndrome (MetS) indicates increased risk for cardiovascular disease and type 2 diabetes. We estimated the overall and ethnic-specific prevalence of MetS and explored the associations of risk factors with MetS among Amerindian, Creole, Hindustani, Javanese, Maroon and Mixed ethnic groups. We used the 2009 Joint Interim Statement (JIS) to define MetS in a subgroup of 2946 participants of the Suriname Health Study, a national survey designed according to the WHO Steps guidelines. The prevalences of MetS and its components were determined for all ethnicities. Hierarchical logistic regressions were used to determine the associations of ethnicity, sex, age, marital status, educational level, income status, employment, smoking status, residence, physical activity, fruit and vegetable intake with MetS. The overall estimated prevalence of MetS was 39.2%. From MetS components, central obesity and low high-density lipoprotein cholesterol (HDL-C) had the highest prevalences. The prevalence of MetS was highest for the Hindustanis (52.7%) and lowest for Maroons (24.2%). The analyses showed that in the overall population sex (women: OR 1.4; 95% CI 1.2 to 1.6), age (OR 5.5 CI 4.3 to 7.2), education (OR 0.7 CI 0.6 to 0.9), living area (OR 0.6 CI 0.5 to 0.8), income (OR 0.7 CI 0.5 to 0.9) and marital status (OR 1.3 CI 1.1 to 1.6) were associated with MetS. Variations observed in the associations of the risk factors with MetS in the ethnic groups did not materially influence the associations of ethnicities with MetS. The prevalence of MetS was high and varied widely among ethnicities. Overall, central obesity and low HDL-C contributed most to MetS. Further studies are needed to assess the prospective associations of risk factors with MetS in different ethnic groups. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

High-molecular weight adiponectin/HOMA-IR ratio as a biomarker of metabolic syndrome in urban multiethnic Brazilian subjects

PubMed Central

de Abreu, Virgínia Genelhu; Martins, Cyro José de Moraes; de Oliveira, Patricia Aguiar Cardoso; Francischetti, Emilio Antonio

2017-01-01

Metabolic syndrome (MetS) has an important epidemiological relevance due to its increasing prevalence and association with type 2 diabetes and cardiovascular disease. Insulin resistance is a core feature of the MetS. HOMA-IR is a robust clinical and epidemiological marker of MetS. Adiponectin is an adipokine with insulin-sensitizing and anti-inflammatory functions; its levels decrease as number of components of MetS increases. High-molecular weight adiponectin (HMWA) is the multimer responsible for the relationship of adiponectin with insulin sensitivity. HOMA-IR and HMWA are suitable candidates for MetS biomarkers. The ratio of adiponectin to HOMA-IR has been validated as a powerful index of MetS and considered a better marker of its presence, than either HOMA-IR or adiponectin alone, in selected homogeneous populations. We compared the strength of association between HMWA, HOMA-IR and HMWA/HOMA-IR ratio with MetS and its key components. Our data have shown that the median (25th, 75th percentile) of HMWA/HOMA-IR ratio was lower in subjects with MetS [0.51 (0.33, 1.31)] as compared to those without it [2.19 (1.13, 4.71)]. The correlation coefficient (r) was significantly higher for HMWA/HOMA-IR ratio as compared to HMWA for waist circumference (-0.65; -0.40, respectively); mean blood pressure (-0.27; -0.14, respectively); fasting glucose (-0.38; -0.19, respectively); HDL-cholesterol (0.44; 0.40, respectively); and triglycerides (-0.35; -0.18, respectively). In a multivariable logistic regression analysis, the HMWA/HOMA-IR ratio was a sensitive predictor for MetS, being the only marker that was significantly associated with each and all the individual components of the syndrome. These results expand on previous studies in that we used the active circulating form of adiponectin, i.e. HMWA, and represent a typical Brazilian cohort characterized by intense interethnic admixture. Thus, the HMWA/HOMA-IR ratio is a minimally invasive biomarker for MetS that could be clinically useful in prognosing patient outcome. PMID:28746378

High-molecular weight adiponectin/HOMA-IR ratio as a biomarker of metabolic syndrome in urban multiethnic Brazilian subjects.

PubMed

de Abreu, Virgínia Genelhu; Martins, Cyro José de Moraes; de Oliveira, Patricia Aguiar Cardoso; Francischetti, Emilio Antonio

2017-01-01

Metabolic syndrome (MetS) has an important epidemiological relevance due to its increasing prevalence and association with type 2 diabetes and cardiovascular disease. Insulin resistance is a core feature of the MetS. HOMA-IR is a robust clinical and epidemiological marker of MetS. Adiponectin is an adipokine with insulin-sensitizing and anti-inflammatory functions; its levels decrease as number of components of MetS increases. High-molecular weight adiponectin (HMWA) is the multimer responsible for the relationship of adiponectin with insulin sensitivity. HOMA-IR and HMWA are suitable candidates for MetS biomarkers. The ratio of adiponectin to HOMA-IR has been validated as a powerful index of MetS and considered a better marker of its presence, than either HOMA-IR or adiponectin alone, in selected homogeneous populations. We compared the strength of association between HMWA, HOMA-IR and HMWA/HOMA-IR ratio with MetS and its key components. Our data have shown that the median (25th, 75th percentile) of HMWA/HOMA-IR ratio was lower in subjects with MetS [0.51 (0.33, 1.31)] as compared to those without it [2.19 (1.13, 4.71)]. The correlation coefficient (r) was significantly higher for HMWA/HOMA-IR ratio as compared to HMWA for waist circumference (-0.65; -0.40, respectively); mean blood pressure (-0.27; -0.14, respectively); fasting glucose (-0.38; -0.19, respectively); HDL-cholesterol (0.44; 0.40, respectively); and triglycerides (-0.35; -0.18, respectively). In a multivariable logistic regression analysis, the HMWA/HOMA-IR ratio was a sensitive predictor for MetS, being the only marker that was significantly associated with each and all the individual components of the syndrome. These results expand on previous studies in that we used the active circulating form of adiponectin, i.e. HMWA, and represent a typical Brazilian cohort characterized by intense interethnic admixture. Thus, the HMWA/HOMA-IR ratio is a minimally invasive biomarker for MetS that could be clinically useful in prognosing patient outcome.

Uncovering Metabolic Syndrome among Chronic Obstructive Pulmonary Disease Patients in a Tertiary Care Hospital, India.

PubMed

Gupta, Kamlesh Kumar; Singh, Jitendra; Gupta, Pradeep; Patel, M L; Kumar, Vivek; Chaudhary, Shyam Chand

2017-05-01

Chronic Obstructive Pulmonary Disease (COPD) is known to cause various systemic problems including Metabolic Syndrome (MetS). MetS is a group of cardiovascular risk factors. By assessing MetS, one can assess the cardiovascular disease risk. There is increasing evidence of MetS in COPD patients. However, the frequency of MetS and its individual components are not still been clearly shown which is likely to vary in different population. To know the extent of association of metabolic syndrome and its components in patients with COPD. This study was designed as an analytical case control study. Ninety cases of COPD satisfying the inclusion criteria and 45 healthy volunteer subjects as controls were recruited over 18 months duration. Simple random sampling method was used to select all cases attending outdoor and indoor medicine department. All subjects (cases and controls) were matched for age, sex, occupation and socioeconomic status. Prior to participation in the study, written informed consent was taken from all subjects. All included subjects underwent a detailed history, clinical examination and laboratorial analysis. All subjects were assessed for MetS by using National Cholesterol Education Program-Third Adult Treatment Panel (NCEP ATP III) and International Diabetic Federation (IDF) criteria. The present study demonstrated Metabolic Syndrome (MetS) in COPD according to NCEP ATP III and IDF criteria as 14 (15.56%) and 30 (33.33%) while there was no association of MetS with controls. The frequency of its component such as abdominal obesity, systolic blood pressure, diastolic blood pressure, elevated triglyceride, reduced HDL-C and elevated fasting glucose respectively was 71 (78.89%), 25 (26.67%), 12 (13.33%), 18 (20%), 23 (25.56%) and 17 (18.78%) respectively. Dyslipidemia was found in 36 (40%) cases of COPD including 16 (17.78%) cases of elevated LDL cholesterol. Our study concluded that MetS is frequent in COPD patients as compared to general population. Therefore, a comprehensive medical approach to screen all COPD patients for MetS should be done there to lower the significant risk of cardiovascular events in patients with COPD.

Cancer chemoprevention research with selenium in the post-SELECT era: Promises and challenges

PubMed Central

Lü, Junxuan; Zhang, Jinhui; Jiang, Cheng; Deng, Yibin; Özten, Nur; Bosland, Maarten C.

2016-01-01

The negative efficacy outcomes of double-blinded, randomized, placebo-controlled Phase III human clinical trials with selenomethionine (SeMet) and SeMet-rich selenized-yeast (Se-yeast) for prostate cancer prevention and Se-yeast for prevention of non-small cell lung cancer (NSCLC) in North America lead to rejection of SeMet/Se-yeast for cancer prevention in Se-adequate populations. We identify two major lessons from the outcomes of these trials: 1) The antioxidant hypothesis was tested in wrong subjects or patient populations. 2) The selection of Se agents was not supported by cell culture and preclinical animal efficacy data as is common in drug development. We propose that next-generation forms of Se (next-gen Se), such as methylselenol precursors, offer biologically appropriate approaches for cancer chemoprevention but these are faced with formidable challenges. Solid mechanism-based preclinical efficacy assessments and comprehensive safety studies with next-gen Se will be essential to re-vitalize the idea of cancer chemoprevention with Se in the post-SELECT era. We advocate smaller mechanism-driven Phase I/II trials with these next-gen Se to guide and justify future decisions for definitive Phase III chemoprevention efficacy trials. PMID:26595411

Cancer chemoprevention research with selenium in the post-SELECT era: Promises and challenges.

PubMed

Lü, Junxuan; Zhang, Jinhui; Jiang, Cheng; Deng, Yibin; Özten, Nur; Bosland, Maarten C

2016-01-01

The negative efficacy outcomes of double-blinded, randomized, placebo-controlled Phase III human clinical trials with selenomethionine (SeMet) and SeMet-rich selenized-yeast (Se-yeast) for prostate cancer prevention and Se-yeast for prevention of nonsmall cell lung cancer (NSCLC) in North America lead to rejection of SeMet/Se-yeast for cancer prevention in Se-adequate populations. We identify 2 major lessons from the outcomes of these trials: 1) the antioxidant hypothesis was tested in wrong subjects or patient populations, and 2) the selection of Se agents was not supported by cell culture and preclinical animal efficacy data as is common in drug development. We propose that next-generation forms of Se (next-gen Se), such as methylselenol precursors, offer biologically appropriate approaches for cancer chemoprevention but these are faced with formidable challenges. Solid mechanism-based preclinical efficacy assessments and comprehensive safety studies with next-gen Se will be essential to revitalize the idea of cancer chemoprevention with Se in the post-SELECT era. We advocate smaller mechanism-driven Phase I/II trials with these next-gen Se to guide and justify future decisions for definitive Phase III chemoprevention efficacy trials.

Genomic status of MET potentiates sensitivity to MET and MEK inhibition in NF1-related malignant peripheral nerve sheath tumors.

PubMed

Peacock, Jacqueline D; Pridgeon, Matthew G; Tovar, Elizabeth A; Essenburg, Curt J; Bowman, Megan J; Madaj, Zachary B; Koeman, Julie; Boguslawski, Elissa A; Grit, Jamie; Dodd, Rebecca D; Khachaturov, Vadim; Cardona, Diana M; Chen, Mark; Kirsch, David G; Maina, Flavio; Dono, Rosanna; Winn, Mary E; Graveel, Carrie R; Steensma, Matthew R

2018-05-02

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly resistant sarcomas that occur in up to 13% of individuals with Neurofibromatosis Type 1 (NF1). Genomic analysis of longitudinally collected tumor samples in a case of MPNST disease progression revealed early hemizygous microdeletions in NF1 and TP53, with progressive amplifications of MET, HGF, and EGFR. To examine the role of MET in MPNST progression, we developed mice with enhanced MET expression and Nf1 ablation (Nf1fl/KO;lox-stop-loxMETtg/+;Plp-creERTtg/+; referred to as NF1 MET). NF1-MET mice express a robust MPNST phenotype in the absence of additional mutations. A comparison of NF1-MET MPNSTs with MPNSTs derived from Nf1KO/+;p53R172H;Plp-creERTtg/+ (NF1-P53) and Nf1KO/+;Plp-creERTtg/+ (NF1) mice revealed unique Met, Ras, and PI3K signaling patterns. NF1-MET MPNSTs were uniformly sensitive to the highly selective MET inhibitor, capmatinib, whereas a heterogeneous response to MET inhibition was observed in NF1-P53 and NF1 MPNSTs. Combination therapy of capmatinib and the MEK inhibitor trametinib resulted in reduced response variability, enhanced suppression of tumor growth, and suppressed RAS/ERK and PI3K/AKT signaling. These results highlight the influence of concurrent genomic alterations on RAS effector signaling and therapy response to tyrosine kinase inhibitors. Moreover, these findings expand our current understanding of the role of MET signaling in MPNST progression and identify a potential therapeutic niche for NF1-related MPNSTs. Copyright ©2018, American Association for Cancer Research.

Study of the Met Tyrosine Kinase in the Pathogenesis of Breast Cancer.

DTIC Science & Technology

1998-10-01

cDNA clones appeared to encode for open reading frames, however, and neither clone showed any homology to the protein Gab1 , which is a signal...domain, and tissue characterization using specific antibodies , will hopefully determine whether these clones represent important c-met targets. In...Behrens J, Birchmeier W. Interaction between Gab1 and the c-met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature 1996;384:173

Endogenous Androgens and Sex Hormone-Binding Globulin in Women and Risk of Metabolic Syndrome and Type 2 Diabetes.

PubMed

Fenske, Benjamin; Kische, Hanna; Gross, Stefan; Wallaschofski, Henri; Völzke, Henry; Dörr, Marcus; Nauck, Matthias; Keevil, Brian G; Brabant, Georg; Haring, Robin

2015-12-01

The association of endogenous androgens and sex hormone-binding globulin (SHBG) with metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) mostly 23562 refers to small and selected study samples with immunoassay-based measurements. Thus, we investigated the association of hormone levels with MetS and T2DM in women from a large population-based sample. A total of 2077 women from the Study of Health in Pomerania were assessed at baseline (N = 3160, 1997-2001) and 5-year follow-up (N = 1711, 2002-2006). We investigated associations of total testosterone (T) and androstenedione measured by liquid chromatography-tandem mass spectrometry, SHBG by immunoassay, and free T and free androgen index with MetS and T2DM. Baseline prevalence of MetS and T2DM was 23.1% (N = 365) and 9.5% (N = 196), with an incidence of 17.7 and 7.0 per 1.000 person-years, respectively. Cross-sectional analyses yielded inverse associations of SHBG with MetS (relative risk [RR], 0.67; 95% confidence interval [CI], 0.60-0.74) and T2DM (RR, 0.61; 95% CI, 0.50-0.74) after multivariable adjustment. In longitudinal analyses, only age-adjusted models showed an inverse association of baseline SHBG with incident MetS (RR, 0.61; 95% CI, 0.51-0.73) and T2DM (RR, 0.58; 95% CI, 0.43-0.78). Multivariable-adjusted models stratified by menopausal status revealed an inverse association between SHBG and incident MetS risk in postmenopausal women (RR, 0.65; 95% CI, 0.51-0.81). This longitudinal population-based study revealed independent inverse associations of SHBG with MetS and T2DM, suggesting low SHBG as a potential risk marker for cardiometabolic morbidity, especially among postmenopausal women.

Kidney function in obese adolescents with or without metabolic syndrome in a nationally-representative sample of pediatric population: First report from the Middle East and North Africa: The CASPIAN-III Study: A Case-Control Study

PubMed Central

Kelishadi, Roya; Gheissari, Alaleh; Bazookar, Neda; Motlagh, Mohammad Esmaeil; Taslimi, Mahnaz; Ardalan, Gelayol

2013-01-01

Background: Obesity in accordance with metabolic syndrome (MetS) confronts populations at the higher risk of morbidity and mortality of chronic diseases including, chronic kidney diseases (CKD). The renal complication of obesity and MetS has been less debated in young adolescents. The objective of this study was to assess the kidney function in obese adolescents with or without MetS. Materials and Methods: The data used in this study were collected as part of a national study entitled Childhood and Adolescence Surveillance and Prevention of Adult Non-communicable disease Study. The present study was conducted on a sub-sample of 113 obese adolescents (body mass index >95th percentile) aged between 10 years and 16 years selected by convenient sampling from the whole population studied. Anthropometric indexes and blood pressure were examined. A 12-h fasting serum was obtained for each participant to measure blood glucose, lipid profile, quantitative C-reactive protein (hs-CRP), Cystatin-c, urea, and creatinine. Fasting spot urine was collected to determine microalbumin and creatinine. Based on the study findings, participants were assigned into two groups with and without MetS. Results: The mean of microalbuminuria was in similar ranges in two groups and while the mean glomerular filtration rate (GFR) calculated by Bokenkamp's, updated and combined Schwartz's formulas were significantly lower in MetS + obese group in comparison with obese group. The similar result was not achieved by Filler's formula. Among MetS components, waist circumference had a correlation with hs-CRP (P = 0.04; r = 0.15). GFR was calculated based on the Schwartz formula and Cystatin-c formulas had no significant correlation with any MetS components. Conclusion: Our findings suggest that MetS can increase the risk of kidney dysfunction in obese adolescents. More studies are suggested in this regard in the pediatric population. PMID:23930111

Evaluation of short-duration, unscheduled absences among transit operators: TriMet case study.

DOT National Transportation Integrated Search

2009-09-01

This report analyzes factors contributing to short duration (one to three days) unscheduled absences among operators at TriMet, the transit provider for the Portland, Oregon metropolitan region. The analysis draws on a wide array of operator-specific...

Evaluation of Xylem EXO water-quality sondes and sensors

USGS Publications Warehouse

Snazelle, Teri T.

2015-01-01

Two models of multiparameter sondes manufactured by Xylem, parent company of Yellow Springs Incorporated (YSI)—EXO1 and EXO2—equipped with EXO conductivity/temperature (C/T), pH, dissolved oxygen (DO), and turbidity sensors, were evaluated by the U.S. Geological Survey (USGS) Hydrologic Instrumentation Facility. The sondes and sensors were evaluated in two phases for compliance with the manufacturer’s specifications and the USGS acceptance criteria for continuous water-quality monitors. Phase one tested the accuracy of the water-quality sondes equipped: (a) with a C/T, pH, DO, and turbidity sensor by comparing the EXO sensors’ measured values to those of an equivalently configured YSI 6920 V2-2 sensor, and (b) with multiple sensors of the same parameter type (such as three pH sensors and a C/T sensor) on a single sonde at room temperature and at an extended temperature range. In addition to accuracy, the communication protocols and the manufacturing specifications for range of detection and operating temperature were also tested during this phase. Phase two evaluated the sondes’ performance in a surface-water environment by deploying an EXO1 and an EXO2 equipped with pH, C/T, DO, and turbidity sensors at USGS site 02492620 located at East Pearl River near Bay Saint Louis, Mississippi. The EXO sondes’ temperature deviations from a certified YSI 4600 digital thermometer were within the ±0.2 degree Celsius (°C) USGS criteria, but were greater than the ±0.01 °C manufacturing specification. The conductivity sensors met the ±3 percent USGS criteria for specific conductance greater than 100 microsiemens per centimeter. The sensors met the more stringent ±0.5 percent manufacturing specification only at room temperature in the 250 microsiemens per centimeter (µS/cm) standard. The manufacturing and USGS criteria (±0.2 pH unit) were met in pH standards 4, 9.2, 10, and 12.45, but were not met in pH 1.68 standard. The DO sensors met both the ±0.3 milligram per liter (mg/L) USGS criteria and the ±1 percent manufacturing specification. The ±5 percent USGS criteria for turbidity in waters not exceeding 2,000 formazin nephelometric units (FNU) were met by the five turbidity sensors tested; however, all five sensors failed to meet these requirements at turbidities exceeding 2,000 FNU. The more stringent ±2 percent manufacturing turbidity specification for water with less than 1,000 FNU was met by only one of the five sensors tested. The results from the field deployment indicated acceptable agreement in temperature, specific conductance, pH, and DO between the EXO sondes, the site sonde, and the reference sonde. The EXO1 and EXO2 turbidity measurements differed from the site sonde by approximately 23 and 25 percent, respectively.

Metabolic syndrome and parental history of cardiovascular disease in young adults in urban Ghana.

PubMed

Yeboah, Kwame; Dodam, Kennedy Konlan; Affrim, Patrick Kormla; Adu-Gyamfi, Linda; Bado, Anormah Rashid; Owusu Mensah, Richard N A; Adjei, Afua Bontu; Gyan, Ben

2017-08-03

Metabolic syndrome (MetS) in young adults poses significant cardiovascular diseases (CVD) risk for later years. Parental history of CVDs is known to affect the prevalence of CVD risk in adulthood. In sub-Saharan Africa, the burden of MetS in young adults and its relationship with parental CVDs is largely unknown. We studied the gender-specific prevalence of MetS and its association with parental history of diabetes, hypertension and CVDs in young adults resident in urban Ghana. In a cross-sectional design, 364 young adults aged 20-30 years were randomly recruited from students of University of Ghana. A structured questionnaire was used to collect data on demography, lifestyle, medical and parental medical history. Anthropometric indices and blood pressures were measured. Fasting blood samples were collected to measure plasma levels of glucose, lipid profile, urea and creatinine. MetS was defined according to the Joint Scientific Statement criteria. The prevalence of MetS was 12.4%, higher in females than male participants (18.4% vs 5.7, p = 0.019). Female participants had higher levels of all the components of MetS than the male participants. Compared to participants with no history of parental CVDs, participants with parental CVDs had a higher proportion of abdominal obesity. A positive history of parental CVDs was associated with increase in odds of MetS [OR (95% CI): 1.23 (1.12-3.04), p = 0.037]. In our study population, there is relatively high prevalence of MetS; higher in females compared to male participants. Parental history of CVDs was associated with MetS.

Working hours and incidence of metabolic syndrome and its components in a Mediterranean cohort: the SUN project.

PubMed

Pimenta, Adriano M; Bes-Rastrollo, Maira; Sayon-Orea, Carmen; Gea, Alfredo; Aguinaga-Ontoso, Enrique; Lopez-Iracheta, Roberto; Martinez-Gonzalez, Miguel A

2015-08-01

Metabolic syndrome (MetS) is an important and priority public health problem globally. Long working hours have been proposed as a modifiable risk factor for MetS, despite sparse epidemiological evidence. Thus, the aim of this study was to prospectively evaluate the associations between working hours and incidence of MetS and each of its components. We assessed 6845 participants of a Spanish dynamic prospective cohort of university graduates (the SUN project), initially free of any specific criteria of MetS, and followed-up for a median of 8.3 years. Weekly working hours were collected at baseline and grouped into four categories: >0-24, 25-39, 40-49 and ≥50 h. MetS was defined according to the updated harmonizing criteria. We estimated multivariable adjusted Relative Risks (RR) of MetS and their 95% Confidence Intervals (95% CI), using Poisson regression models. The cumulative incidence of MetS was 6.0%. Working hours were not independently related to MetS (25-39 h/week = RR: 1.42, 95% CI 0.90-2.25; 40-49 h/week = RR: 1.45, 95% CI 0.91-2.30; ≥50 h/week = RR: 1.49, 95% CI 0.91-2.42, P for trend = 0.235) nor to any of its individual definition criteria. Our findings do not suggest that long working hours increase the risk of MetS development or each of its components. Further longitudinal studies in general population should be conducted to confirm these results. © The Author 2015. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.

Relationship of Body Anthropometry with Cardiovascular Risk Factors in a Random Community Sample: The Phoenix Lifestyle Project.

PubMed

Duki, Yajna; Naidoo, Datshana P

2016-03-01

We studied the prevalence of metabolic syndrome (MetS) among Indians from a low-income community and evaluated the relationship between physical behavior patterns and anthropometric measures and the presence of MetS. The modified WHO STEPS questionnaire was used to collect data from a randomized sample of 1154 subjects from the Indian community of Phoenix, Durban. MetS was classified according to the harmonized criteria. The median age of the sample was 47 (37-55) years, and 72% were predominantly females. There was a high prevalence of elevated body mass index (BMI) in 757 subjects (66%), which increased to 901 subjects (82%) when the ethnic-specific Asian cutoff (BMI ≥ 23) was applied. Overall increase in waist circumferences was noted from 60% to 79% when ethnic cutoffs were applied. Vigorous exercise was associated with a significant decrease in waist and BMI measurements (P < 0.0001). The prevalence of MetS increased from 30% and 57% (NCEP) to 45% and 60% in males and females, respectively, when the harmonized criteria (IDF and WHO) were applied. Fasting insulin and total cholesterol emerged as independent determinants of MetS for both genders. Neck circumference and HbA1c were also significant predictors of MetS in males. In females, midarm circumference (IDF/WHO) and HbA1c (modified NCEP) emerged as additional predictors of MetS. There was a high prevalence of obesity and MetS in this sample, related to sedentary behavior patterns. Neck and arm circumferences as well as total cholesterol may also serve as screening measures to increase the detection rate of MetS.

Association Between Sarcopenia and Metabolic Syndrome in Cancer Survivors.

PubMed

Lee, Su Jung; Kim, Nam Cho

Advanced cancer treatments have improved survival from cancer, but the incidence of cardiovascular disease in survivors has recently increased. Sarcopenia and metabolic syndrome (MetS) are related to cancer survival, and sarcopenia is an emerging risk factor for cardiovascular disease. However, evidence of a relationship between sarcopenia and MetS in cancer survivors is lacking. The aims of this study were to determine the prevalence of sarcopenia and MetS in cancer survivors and to investigate independent predictors of MetS in cancer survivors. From the fourth and fifth Korea National Health and Nutritional Exam Survey (2008-2011), 798 consecutive cancer survivors were analyzed. Sarcopenia was defined as the appendicular skeletal muscle mass divided by weight less than 1 SD below the sex-specific healthy population aged 20 to 39 years. Metabolic syndrome was defined using the National Cholesterol Education Program definition. Among 798 cancer survivors, the prevalence rates of sarcopenia and MetS were 23.1% and 30.0%, respectively. Survivors with sarcopenia were more likely to have a higher waist circumference, body mass index, triglyceride level, and blood pressure and to have a lower high-density lipoprotein cholesterol level compared with those without sarcopenia. In multivariable analysis, sarcopenia was an independent predictor of MetS (odds ratio, 2.76; 95% confidence interval, 1.92-3.97). In addition, age and type of cancer were independent predictors of MetS. Sarcopenia was associated with an increased prevalence of MetS in cancer survivors. Interventions to prevent sarcopenia may be necessary to improve cardiovascular outcome in cancer survivors.

7 CFR 246.5 - Selection of local agencies.

Code of Federal Regulations, 2010 CFR

2010-01-01

... consider how much of the current need is being met at each priority level. The selection criteria cited in... 7 Agriculture 4 2010-01-01 2010-01-01 false Selection of local agencies. 246.5 Section 246.5 Agriculture Regulations of the Department of Agriculture (Continued) FOOD AND NUTRITION SERVICE, DEPARTMENT OF...

Tachykinin receptors in the small intestine of the cane toad (Bufo marinus): a radioligand binding and functional study.

PubMed

Burcher, E; Warner, F J

1998-06-01

In this study, we have used radioligand binding and functional techniques to investigate tachykinin receptors in the small intestine of the cane toad Bufo marinus. The radioligand [125I]Bolton-Hunter [Sar9,Met(O2)11]substance P (selective at mammalian NK-1 receptors) showed no specific binding. Specific binding of [125I]Bolton-Hunter substance P ([125I]BHSP) was saturable, of high affinity (Kd 0.3 nM) and was inhibited by SP (IC50 0.64 nM) > ranakinin approximately neurokinin A (NKA) > or = SP(5-11) > or = neuropeptide gamma > or = scyliorhinin II > scyliorhinin I > or = [Sar9]-SP > or = neurokinin B approximately physalaemin approximately carassin > SP(7-11) approximately eledoisin > or = SP(4-11) approximately SP(6-11). Binding was also inhibited by Gpp[NH]p > or = GTPgammaS > App[NH]p, indicating a G-protein coupled receptor. The order of potency of tachykinins and analogues in contracting the isolated lower small intestine was carassin (EC50 1.4 nM) > eledoisin approximately SP > or = physalaemin > or = ranakinin > SP(6-11) > scyliorhinin II > or = neuropeptide gamma > neurokinin B approximately NKA approximately scyliorhinin I > or = SP(4-11) > or = SP(5-11) > [Sar9]SP > SP(7-11). In both studies, the selective mammalian NK-1, NK-2 and NK-3 receptor agonists [Sar9,Met(O2)11]SP, [Lys5,Me-Leu9,Nle10]NKA(4-10) and senktide were weak or ineffective. There was a strong positive correlation between the pD2 and pIC50 values for mammalian tachykinins and analogues (r = 0.907), but not for the non-mammalian tachykinins, which were all full agonists but variable binding competitors. [Sar9,Met(O2)11]-SP(pD2 5.7) was approximately 25-fold less potent as an agonist than [Sar9]SP, which was itself 25-fold weaker than SP. Responses to SP were significantly reduced (n = 8, P<0.001) by the antagonist [D-Arg1,D-Trp7,9,Leu11]-SP (spantide; 1 microM). Highly selective NK-1 receptor antagonists including CP 99994 and GR 82334 (both 1 microM) were ineffective in both functional and binding studies. Tetrodotoxin (1 microM) did not inhibit contractile responses to SP, NKA and senktide. In summary, this study has shown the presence of one or more tachykinin receptor in the toad intestine. The binding site recognised by [125I]BHSP prefers SP and ranakinin. This toad "NK-1-like receptor" differs from the mammalian NK-1 receptor in having a low affinity for all mammalian NK-1 selective ligands, including antagonists. For some non-mammalian peptides, their high potency as contractile agonists relative to their poor binding affinity suggests the existence of other tachykinin receptors in the toad small intestine.

Heritability of the Severity of the Metabolic Syndrome in Whites and Blacks in 3 Large Cohorts.

PubMed

Musani, Solomon K; Martin, Lisa J; Woo, Jessica G; Olivier, Michael; Gurka, Matthew J; DeBoer, Mark D

2017-04-01

Although dichotomous criteria for the metabolic syndrome (MetS) appear heritable, it is not known whether MetS severity as assessed by a continuous MetS score is heritable and whether this varies by race. We used SOLAR (Sequential Oligogenic Linkage Analysis Routines) to evaluate heritability of Adult Treatment Panel-III MetS and a sex- and race-specific MetS severity Z score among 3 large familial cohorts: the JHS (Jackson Heart Study, 1404 black participants), TOPS (Take Off Pounds Sensibly, 1947 white participants), and PLRS (Princeton Lipid Research Study, 229 black and 527 white participants). Heritability estimates were larger for Adult Treatment Panel-III MetS among black compared with white cohort members (JHS 0.48; 95% confidence interval [CI], 0.28-0.68 and PLRS blacks 0.93 [95% CI, 0.73-1.13] versus TOPS 0.21 [95% CI, -0.18 to 0.60] and PLRS whites 0.27 [95% CI, -0.04 to 0.58]). The difference by race narrowed when assessing heritability of the MetS severity score (JHS 0.52 [95% CI, 0.38, 0.66] and PLRS blacks 0.64 [95% CI, 0.13-1.15] versus TOPS 0.23 [95% CI, 0.15-0.31] and PLRS whites 0.60 [95% CI, 0.33-0.87]). There was a high degree of genetic and phenotypic correlation between MetS severity and the individual components of MetS among all groups, although the genetic correlations failed to reach statistical significance among PLRS blacks. Meta-analyses revealed a combined heritability estimate for Adult Treatment Panel-III MetS of 0.24 (95% CI, 0.11-0.36) and for the MetS severity score of 0.50 (95% CI, -0.05 to 0.99). MetS severity seems highly heritable among whites and blacks. This continuous MetS severity Z score may provide a more useful means of characterizing phenotypic MetS in genetic studies by minimizing racial differences. © 2017 American Heart Association, Inc.

Associations of unprotected anal intercourse with Grindr-met partners among Grindr-using young men who have sex with men in Los Angeles.

PubMed

Winetrobe, Hailey; Rice, Eric; Bauermeister, Jose; Petering, Robin; Holloway, Ian W

2014-01-01

Grindr, a geosocial smartphone application, is a networking medium for men who have sex with men. Although three quarters of young men who have sex with men (YMSM) Grindr users report having sex with a Grindr-met partner, the correlates of risky sexual behavior with Grindr-met partners are unknown. A randomly selected sample of 18- to 24-year-old, Grindr-using YMSM completed an anonymous online questionnaire assessing patterns of Grindr use and sexual behavior with their last Grindr-met partners. Of the 146 YMSM who reported having sex with Grindr-met partners, 20% had unprotected anal intercourse (UAI) at last sex with their Grindr-met partner. In the multivariable model, YMSM who used Grindr for at least one year showed naked chest/abs in their profile photo, and reported more past month Grindr-met partners were more likely to report UAI. These findings suggest that familiarity with the app was associated with YMSM's UAI with Grindr-met partners. Moreover, sexualized profile photos (i.e., naked chest/abs) may be associated with sexual risk-taking behaviors. HIV prevention interventions delivered or linked through such apps should target individuals who are longer/frequent users and who present sexualized profiles.

A peptide representing the carboxyl-terminal tail of the met receptor inhibits kinase activity and invasive growth.

PubMed

Bardelli, A; Longati, P; Williams, T A; Benvenuti, S; Comoglio, P M

1999-10-08

Interaction of the hepatocyte growth factor (HGF) with its receptor, the Met tyrosine kinase, results in invasive growth, a genetic program essential to embryonic development and implicated in tumor metastasis. Met-mediated invasive growth requires autophosphorylation of the receptor on tyrosines located in the kinase activation loop (Tyr(1234)-Tyr(1235)) and in the carboxyl-terminal tail (Tyr(1349)-Tyr(1356)). We report that peptides derived from the Met receptor tail, but not from the activation loop, bind the receptor and inhibit the kinase activity in vitro. Cell delivery of the tail receptor peptide impairs HGF-dependent Met phosphorylation and downstream signaling. In normal and transformed epithelial cells, the tail receptor peptide inhibits HGF-mediated invasive growth, as measured by cell migration, invasiveness, and branched morphogenesis. The Met tail peptide inhibits the closely related Ron receptor but does not significantly affect the epidermal growth factor, platelet-derived growth factor, or vascular endothelial growth factor receptor activities. These experiments show that carboxyl-terminal sequences impair the catalytic properties of the Met receptor, thus suggesting that in the resting state the nonphosphorylated tail acts as an intramolecular modulator. Furthermore, they provide a strategy to selectively target the MET proto-oncogene by using small, cell-permeable, peptide derivatives.

Prevalence of metabolic syndrome and its risk factors in adult Malaysians: results of a nationwide survey.

PubMed

Mohamud, Wan Nazaimoon Wan; Ismail, Aziz al-Safi; Khir, Amir Sharifuddin Md; Ismail, Ikram Shah; Musa, Kamarul Imran; Kadir, Khalid Abdul; Kamaruddin, Nor Azmi; Yaacob, Nor Azwany; Mustafa, Norlaila; Ali, Osman; Isa, Siti Harnida Md; Bebakar, Wan Mohamad Wan

2012-04-01

Aim: To report the national prevalence of metabolic syndrome (MetS) and its risk factors among adult Malaysians (>18 years old) based on World Health Organization (WHO), the National Cholesterol Education Program Expert Panel III (ATP III), International Diabetes Federation (IDF) and the 'Harmonized' criteria.Methods: A multi-stage stratified sampling method was used to select 4341 subjects from Peninsular and East Malaysia. Subjects underwent physical and clinical examinations.Results: Based on the WHO, ATP III, IDF and Harmonized definitions, the overall crude prevalences of MetS were 32.1, 34.3, 37.1 and 42.5%, respectively. Regardless of the criteria used, MetS was higher in urban areas, in females, in the Indian population and increased significantly with age. Risk factors also increased with age; abdominal obesity was most prevalent (57.4%), was higher in females (64.2%) and was highest in Indians (68.8%).Hypertension was higher in males (56.5%) and highest among Malays (52.2%). In contrast,the Chinese had the highest prevalence of hypertriglyceridemia (47.4%).Conclusions: Malaysia has a much higher prevalence of MetS compared with other Asian countries and, unless there is immediate intervention to reduce risk factors, this may pose serious implications on the country's healthcare costs and services.

Prevalence of metabolic syndrome and its risk factors in adult Malaysians: results of a nationwide survey.

PubMed

Mohamud, Wan Nazaimoon Wan; Ismail, Aziz Al-Safi; Sharifuddin, Amir; Ismail, Ikram Shah; Musa, Kamarul Imran; Kadir, Khalid Abdul; Kamaruddin, Nor Azmi; Yaacob, Nor Azwany; Mustafa, Norlaila; Ali, Osman; Harnida, Siti; Bebakar, Wan Mohamad Wan

2011-02-01

To report the national prevalence of metabolic syndrome (MetS) and its risk factors among adult Malaysians (>18 years old) based on World Health Organization (WHO), the National Cholesterol Education Program Expert Panel III (ATP III)(,) International Diabetes Federation (IDF) and the 'Harmonized' criteria. A multi-stage stratified sampling method was used to select 4341 subjects from Peninsular and East Malaysia. Subjects underwent physical and clinical examinations. Based on the WHO, ATP III, IDF and Harmonized definitions, the overall crude prevalences of MetS were 32.1, 34.3, 37.1 and 42.5%, respectively. Regardless of the criteria used, MetS was higher in urban areas, in females, in the Indian population and increased significantly with age. Risk factors also increased with age; abdominal obesity was most prevalent (57.4%), was higher in females (64.2%) and was highest in Indians (68.8%). Hypertension was higher in males (56.5%) and highest among Malaysians (52.2%). In contrast, the Chinese had the highest prevalence of hypertriglyceridaemia (47.4%). Malaysia has a much higher prevalence of MetS compared with other Asian countries and, unless there is immediate intervention to reduce risk factors, this may pose serious implications on the country's healthcare costs and services. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

APOC3 Promoter Polymorphisms C-482T and T-455C Are Associated with the Metabolic Syndrome1

PubMed Central

Miller, Michael; Rhyne, Jeffrey; Chen, Hegang; Beach, Valerie; Ericson, Richard; Luthra, Kalpana; Dwivedi, Manjari; Misra, Anoop

2007-01-01

Background Despite the growing epidemic of the metabolic syndrome (MetS), few studies have evaluated genetic polymorphisms associated with the MetS phenotype. One candidate, APOC3, modulates lipid and lipoprotein metabolism and the promoter polymorphisms C-482T/T-455C are associated with loss of insulin downregulation. Methods One hundred twenty two consecutive MetS cases were matched by age, sex and race in a 1:1 case-control design to evaluate the prevalence of common polymorphisms in the following candidate genes: APOC3, APOE, B3AR, FABP2, GNB3, LPL, and PPARα and PPARγ. Results Compared to controls, MetS subjects exhibited a greater prevalence of APOC3 promoter polymorphisms. Specifically, the frequency of the variant C-482T and T-455C alleles was 70.5 and 81.9% of cases compared to 43.4 and 54.1% in controls, respectively ( p <0.0001). Overall, APOC3 promoter variants were associated with a greater likelihood of MetS compared to wild type [C-482T (OR: 4.3; 95% CI: 2.2, 8.6 [p <0.0001]), T-455C (OR: 3.6; 95% CI: 2.0, 6.7 [p <0.0001])]. No material differences were identified between the other genetic variants tested and prevalence of MetS. Conclusions These data, therefore, suggest that the APOC3 promoter polymorphisms C-482T and T-455C are associated with the MetS. PMID:17416293

APOC3 promoter polymorphisms C-482T and T-455C are associated with the metabolic syndrome.

PubMed

Miller, Michael; Rhyne, Jeffrey; Chen, Hegang; Beach, Valerie; Ericson, Richard; Luthra, Kalpana; Dwivedi, Manjari; Misra, Anoop

2007-05-01

Despite the growing epidemic of the metabolic syndrome (MetS), few studies have evaluated genetic polymorphisms associated with the MetS phenotype. One candidate, APOC3, modulates lipid and lipoprotein metabolism and the promoter polymorphisms C-482T/T-455C are associated with loss of insulin downregulation. One hundred twenty two consecutive MetS cases were matched by age, sex and race in a 1:1 case-control design to evaluate the prevalence of common polymorphisms in the following candidate genes: APOC3, APOE, B3AR, FABP2, GNB3, LPL, and PPARalpha and PPARgamma. Compared to controls, MetS subjects exhibited a greater prevalence of APOC3 promoter polymorphisms. Specifically, the frequency of the variant C-482T and T-455C alleles was 70.5 and 81.9% of cases compared to 43.4 and 54.1% in controls, respectively (p <0.0001). Overall, APOC3 promoter variants were associated with a greater likelihood of MetS compared to wild type [C-482T (OR: 4.3; 95% CI: 2.2, 8.6 [p <0.0001]), T-455C (OR: 3.6; 95% CI: 2.0, 6.7 [p <0.0001])]. No material differences were identified between the other genetic variants tested and prevalence of MetS. These data, therefore, suggest that the APOC3 promoter polymorphisms C-482T and T-455C are associated with the MetS.

Psychosocial Predictors of Metabolic Syndrome among Latino Groups in the Multi-Ethnic Study of Atherosclerosis (MESA)

PubMed Central

Ortiz, Manuel S.; Myers, Hector F.; Dunkel Schetter, Christine; Rodriguez, Carlos J.; Seeman, Teresa E.

2015-01-01

Objective We sought to determine the contribution of psychological variables to risk for metabolic syndrome (MetS) among Latinos enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA), and to investigate whether social support moderates these associations, and whether inflammatory markers mediate the association between psychological variables and MetS. Research design and methods Cross-sectional analyses at study baseline were conducted with a national Latino cohort (n = 1,388) that included Mexican Americans, Dominican Americans, Puerto Rican Americans and Central/South Americans. Hierarchical logistic regression analyses were conducted to test the effects of psychosocial variables (chronic stress, depressive symptoms, and social support) on MetS. In addition, separate subgroup-specific models, controlling for nationality, age, gender, socioeconomic position, language spoken at home, exercise, smoking and drinking status, and testing for the effects of chronic stress, depressive symptoms and inflammation (IL-6, CRP, fibrinogen) in predicting risk for MetS were conducted. Results In the overall sample, high chronic stress independently predicted risk for MetS, however this association was found to be significant only in Mexican Americans and Puerto Rican Americans. Social support did not moderate the associations between chronic stress and MetS for any group. Chronic stress was not associated with inflammatory markers in either the overall sample or in each group. Conclusions Our results suggest a differential contribution of chronic stress to the prevalence of MetS by national groups. PMID:25906072

Variations of six transmembrane epithelial antigen of prostate 4 (STEAP4) gene are associated with metabolic syndrome in a female Uygur general population.

PubMed

Nanfang, Li; Yanying, Guo; Hongmei, Wang; Zhitao, Yan; Juhong, Zhang; Ling, Zhou; Wenli, Luo

2010-08-01

Metabolic syndrome (MetS) is linked with visceral obesity and is associated with a clustering of abnormalities (including impaired glucose tolerance, insulin resistance, dyslipidemia and hypertension). Six transmembrane epithelial antigen of prostate 4 (STEAP4) was associated with human obesity. STEAP4 gene represents a strong biological and positional candidate for a susceptibility factor for MetS. Uygur Chinese is a relatively isolated population with a relatively homogeneous environment and a high prevalence of MetS. We undertook this study to investigate the relationship between STEAP4 gene variations and MetS in a Uygur general population. The functional regions of STEAP4 gene were sequenced in Uygur patients with MetS. Four representative variations, rs1981529, rs34741656, rs8122 and 6031T/G (unsuccessfully genotyped), selected with a r² cutoff of 0.8 and minor allele frequency of >5%, were genotyped in 858 MetS and 687 non-MetS controls. Fourteen novel and six known single nucleotide polymorphisms (SNPs) including 2 nonsynonymous SNPs in the STEAP4 gene were identified. SNPs rs8122 and rs1981529 were significantly associated with MetS phenotype in females [additive p = 0.032 and p = 0.011; ORs (95% CI) adjusted for age 0.772 (0.625-0.954) and 0.740 (0.582-0.941), respectively]. Two common haplotypes 1 (rs8122/rs1981529/rs34741656, G-A-G) and 2 (A-G-G) had significantly higher (permutation p = 0.044) and lower (permutation p = 0.009) frequency in MetS than that in controls in females. Multiple linear regression analysis revealed a significant association of the SNPs rs8122 and rs1981529 with HDL-c level in MetS cases (p = 0.001 and 0.024) and in a combined sample (p = 0.004 and 0.009). STEAP4 genetic variations are likely to be associated with metabolic syndrome in a female Uygur general population. Copyright © 2010 IMSS. Published by Elsevier Inc. All rights reserved.

Field Testing and Load Rating Report for Bridge No. 4, Hybrid Composite Beam Span, at Fort Knox, Kentucky

DTIC Science & Technology

2016-09-01

required load rating (HL-93) and performance criteria for deflection and strain. Results showed the bridge met all design specifications and load...their respective owners. The findings of this report are not to be construed as an official Department of the Army position unless so designated by...composite beams met design specifications and could deliver safe crossing of Heavy Equipment Transport System (HETS-115) vehicles. Their report

Inhibition of c-Met reduces lymphatic metastasis in RIP-Tag2 transgenic mice

PubMed Central

Sennino, Barbara; Ishiguro-Oonuma, Toshina; Schriver, Brian J.; Christensen, James G.; McDonald, Donald M.

2013-01-01

Inhibition of vascular endothelial growth factor (VEGF) signaling can promote lymph node metastasis in preclinical models, but the mechanism is not fully understood, and successful methods of prevention have not been found. Signaling of hepatocyte growth factor (HGF) and its receptor c-Met can promote the growth of lymphatics and metastasis of some tumors. We sought to explore the contributions of c-Met signaling to lymph node metastasis after inhibition of VEGF signaling. In particular, we examined whether c-Met is upregulated in lymphatics in or near pancreatic neuroendocrine tumors in RIP-Tag2 transgenic mice and whether lymph node metastasis can be reduced by concurrent inhibition of VEGF and c-Met signaling. Inhibition of VEGF signaling by anti-VEGF antibody or sunitinib in mice from age 14 to 17 weeks was accompanied by more intratumoral lymphatics, more tumor cells inside lymphatics, and more lymph node metastases. Under these conditions, lymphatic endothelial cells - like tumor cells - had strong immunoreactivity for c-Met and phospho-c-Met. c-Met blockade by the selective inhibitor PF-04217903 significantly reduced metastasis to local lymph nodes. Together, these results indicate that inhibition of VEGF signaling in RIP-Tag2 mice upregulates c-Met expression in lymphatic endothelial cells, increases the number of intratumoral lymphatics and number of tumor cells within lymphatics, and promotes metastasis to local lymph nodes. Prevention of lymph node metastasis by PF-04217903 in this setting implicates c-Met signaling in tumor cell spread to lymph nodes. PMID:23576559

Gender effects of the COMT Val 158 Met genotype on verbal fluency in healthy adults.

PubMed

Soeiro-De-Souza, Marcio Gerhardt; Bio, Danielle Soares; David, Denise Petresco; Missio, Giovani; Lima, Bruno; Fernandes, Fernando; Machado-Vieira, Rodrigo; Moreno, Ricardo Alberto

2013-09-01

Cognitive performance in healthy individuals is associated with gender differences in specific tests; a female advantage has been demonstrated in language tests, whereas a male advantage has been demonstrated in spatial relation examinations. The prefrontal cortex (PFC) mediates important cognitive domains and is influenced by dopamine (DA) activity. The single nucleotide polymorphism (SNP) rs4680 in the catechol‑O‑methyltransferase (COMT) gene results in an amino acid substitution from valine (Val) to methionine (Met). The Met allele has been demonstrated to decrease COMT enzyme activity and improve PFC cognitive function. COMT regulates DA activity in the PFC and exhibits gender effects. The aim of the present study was to investigate the gender‑specific effects of the COMT genotype on cognition in healthy young adults. Seventy‑six healthy subjects were genotyped for COMT rs4680 and submitted to an extensive range of neuropsychological tests assessing aspects of PFC function. The COMT Met allele influenced the performance of executive function. The results revealed gender effects of the COMT rs4680 Met allele on verbal fluency, with positive effects in males and negative effects in females. This suggested that DA activity affects cognitive function in different ways, according to gender.

Safety and Efficacy of Intratumoral Injections of Chimeric Antigen Receptor (CAR) T Cells in Metastatic Breast Cancer.

PubMed

Tchou, Julia; Zhao, Yangbing; Levine, Bruce L; Zhang, Paul J; Davis, Megan M; Melenhorst, Jan Joseph; Kulikovskaya, Irina; Brennan, Andrea L; Liu, Xiaojun; Lacey, Simon F; Posey, Avery D; Williams, Austin D; So, Alycia; Conejo-Garcia, Jose R; Plesa, Gabriela; Young, Regina M; McGettigan, Shannon; Campbell, Jean; Pierce, Robert H; Matro, Jennifer M; DeMichele, Angela M; Clark, Amy S; Cooper, Laurence J; Schuchter, Lynn M; Vonderheide, Robert H; June, Carl H

2017-12-01

Chimeric antigen receptors (CAR) are synthetic molecules that provide new specificities to T cells. Although successful in treatment of hematologic malignancies, CAR T cells are ineffective for solid tumors to date. We found that the cell-surface molecule c-Met was expressed in ∼50% of breast tumors, prompting the construction of a CAR T cell specific for c-Met, which halted tumor growth in immune-incompetent mice with tumor xenografts. We then evaluated the safety and feasibility of treating metastatic breast cancer with intratumoral administration of mRNA-transfected c-Met-CAR T cells in a phase 0 clinical trial (NCT01837602). Introducing the CAR construct via mRNA ensured safety by limiting the nontumor cell effects (on-target/off-tumor) of targeting c-Met. Patients with metastatic breast cancer with accessible cutaneous or lymph node metastases received a single intratumoral injection of 3 × 10 7 or 3 × 10 8 cells. CAR T mRNA was detectable in peripheral blood and in the injected tumor tissues after intratumoral injection in 2 and 4 patients, respectively. mRNA c-Met-CAR T cell injections were well tolerated, as none of the patients had study drug-related adverse effects greater than grade 1. Tumors treated with intratumoral injected mRNA c-Met-CAR T cells were excised and analyzed by immunohistochemistry, revealing extensive tumor necrosis at the injection site, cellular debris, loss of c-Met immunoreactivity, all surrounded by macrophages at the leading edges and within necrotic zones. We conclude that intratumoral injections of mRNA c-Met-CAR T cells are well tolerated and evoke an inflammatory response within tumors. Cancer Immunol Res; 5(12); 1152-61. ©2017 AACR . ©2017 American Association for Cancer Research.

Adiponectin/(FBG × FIns) as a predictor of insulin sensitivity and metabolic syndrome in patients with polycystic ovary syndrome

PubMed Central

Xu, Xiaohui; Lai, Yerui; Yang, Gangyi; Yang, Mengliu; Li, Ling; Zhang, Qin; Liu, Hua; Zheng, Hongting; Zhu, Danping

2016-01-01

Abstract The euglycemic–hyperinsulinemic clamp is not available in most clinical settings. An accessible and inexpensive measurement for identifying insulin resistance (IR) is necessary. Our aim is to assess whether the adiponectin (ADI) index (ADI/[FBG × FIns]) is a better surrogate index for the assessment of IR or metabolic syndrome (MetS). A population-based cross-sectional study was conducted including 100 healthy women and 99 polycystic ovary syndrome patients. The euglycemic–hyperinsulinemic clamp was performed. Circulating ADI levels were determined by ELISA. Polycystic ovary syndrome and polycystic ovary syndrome plus MetS subjects had higher products of fasting triglycerides and glucose (TyG), Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), increased ratios of the area under the curve for insulin/the area under the curve for glucose (AUCi/AUCg), but lower ADI index as compared with healthy subjects. Partial correlation analysis in all populations showed that the M-value was significantly negatively correlated with HOMA-IR, TyG, TG/HDL, and AUCi/AUCg, and correlated positively with the ADI index. The r value of Pearson correlation between the ADI index and M-value was greater than that of the correlation between HOMA-IR, TyG, TG/HDL-C, and AUCi/AUCg. The optimal cut-off value of the ADI index for detection of IR was 0.67, with a sensitivity of 89.4% and a specificity of 88.1%, whereas for detection of MetS, it was 0.32, with a sensitivity of 88.7% and a specificity of 71.0%. The ADI index may be a surrogate marker in detecting IR and MetS. PMID:27930544

Novel strategy for a bispecific antibody: induction of dual target internalization and degradation.

PubMed

Lee, J M; Lee, S H; Hwang, J-W; Oh, S J; Kim, B; Jung, S; Shim, S-H; Lin, P W; Lee, S B; Cho, M-Y; Koh, Y J; Kim, S Y; Ahn, S; Lee, J; Kim, K-M; Cheong, K H; Choi, J; Kim, K-A

2016-08-25

Activation of the extensive cross-talk among the receptor tyrosine kinases (RTKs), particularly ErbB family-Met cross-talk, has emerged as a likely source of drug resistance. Notwithstanding brilliant successes were attained while using small-molecule inhibitors or antibody therapeutics against specific RTKs in multiple cancers over recent decades, a high recurrence rate remains unsolved in patients treated with these targeted inhibitors. It is well aligned with multifaceted properties of cancer and cross-talk and convergence of signaling pathways of RTKs. Thereby many therapeutic interventions have been actively developed to overcome inherent or acquired resistance. To date, no bispecific antibody (BsAb) showed complete depletion of dual RTKs from the plasma membrane and efficient dual degradation. In this manuscript, we report the first findings of a target-specific dual internalization and degradation of membrane RTKs induced by designed BsAbs based on the internalizing monoclonal antibodies and the therapeutic values of these BsAbs. Leveraging the anti-Met mAb able to internalize and degrade by a unique mechanism, we generated the BsAbs for Met/epidermal growth factor receptor (EGFR) and Met/HER2 to induce an efficient EGFR or HER2 internalization and degradation in the presence of Met that is frequently overexpressed in the invasive tumors and involved in the resistance against EGFR- or HER2-targeted therapies. We found that Met/EGFR BsAb ME22S induces dissociation of the Met-EGFR complex from Hsp90, followed by significant degradation of Met and EGFR. By employing patient-derived tumor models we demonstrate therapeutic potential of the BsAb-mediated dual degradation in various cancers.

Clustering high-dimensional mixed data to uncover sub-phenotypes: joint analysis of phenotypic and genotypic data.

PubMed

McParland, D; Phillips, C M; Brennan, L; Roche, H M; Gormley, I C

2017-12-10

The LIPGENE-SU.VI.MAX study, like many others, recorded high-dimensional continuous phenotypic data and categorical genotypic data. LIPGENE-SU.VI.MAX focuses on the need to account for both phenotypic and genetic factors when studying the metabolic syndrome (MetS), a complex disorder that can lead to higher risk of type 2 diabetes and cardiovascular disease. Interest lies in clustering the LIPGENE-SU.VI.MAX participants into homogeneous groups or sub-phenotypes, by jointly considering their phenotypic and genotypic data, and in determining which variables are discriminatory. A novel latent variable model that elegantly accommodates high dimensional, mixed data is developed to cluster LIPGENE-SU.VI.MAX participants using a Bayesian finite mixture model. A computationally efficient variable selection algorithm is incorporated, estimation is via a Gibbs sampling algorithm and an approximate BIC-MCMC criterion is developed to select the optimal model. Two clusters or sub-phenotypes ('healthy' and 'at risk') are uncovered. A small subset of variables is deemed discriminatory, which notably includes phenotypic and genotypic variables, highlighting the need to jointly consider both factors. Further, 7 years after the LIPGENE-SU.VI.MAX data were collected, participants underwent further analysis to diagnose presence or absence of the MetS. The two uncovered sub-phenotypes strongly correspond to the 7-year follow-up disease classification, highlighting the role of phenotypic and genotypic factors in the MetS and emphasising the potential utility of the clustering approach in early screening. Additionally, the ability of the proposed approach to define the uncertainty in sub-phenotype membership at the participant level is synonymous with the concepts of precision medicine and nutrition. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Cell membrane organization is important for inner hair cell MET-channel gating

NASA Astrophysics Data System (ADS)

Effertz, Thomas; Scharr, Alexandra L.; Ricci, Anthony J.

2018-05-01

Specialized sensory cells, hair cells, translate mechanical stimuli into electro/chemical responses. This process, termed mechano-electrical transduction (MET), is localized to the hair cell's sensory organelle, the hair bundle. The mature hair bundle comprises three rows of actin filled stereocilia, arranged in a staircase pattern. Deflections towards the tallest row of stereocilia activate MET channels, residing at the top of stereocilia. While other MET channels can be activated or modulated by changes to their lipid environment, this remains unknown for the mammalian auditory MET channel. We show here that the effect of lipid and cholesterol depletion from the cell membrane affect the MET current as well. We used γ-cyclodextrin to extract lipids form the membrane, reversibly reducing the peak MET current, current adaptation, and decreasing the channels resting open probability. The recovery after γ-cyclodextrin treatment was slower than the initial peak current reduction, suggesting that a specific lipid organization is required for normal MET channel function, which requires time reestablish. Extraction of cholesterol, using Mβ-cyclodextrin, irreversibly reduces the peak MET current and reversibly increases the channel resting open probability, suggesting that cholesterol restricts MET channel opening. This restriction could be useful to increase the channel's signal to noise ratio. Together this data suggests that the cell membrane is part of the force relay machinery to the MET channel and could possibly restrict gating associated conformational changes of the MET channel.

Relationship Between Carotid Intima-Media Thickness with some Inflammatory Biomarkers, Ghrelin and Adiponectin in Iranians with and without Metabolic Syndrome in Isfahan Cohort Study

PubMed Central

Hajmohammadi, Taiebeh; Sadeghi, Masoumeh; Dashti, Masoumeh; Hashemi, Mohammad; Saadatnia, Mohammad; Soghrati, Mojgan; Talaei, Mohammad; Sarrafzadegan, Nizal

2010-01-01

BACKGROUND Recent studies have confirmed inflammatory factors and metabolic syndrome (MetS) as important cardiovascular disease (CVD) risk factors. Recently measurement of carotid intima-media thickness (IMT) has been used for evaluation of early atherosclerosis. This study was designed to assess the correlation between IMT with some inflammatory biomarkers, ghrelin and adiponectin in people with and without MetS in a cohort sample in Isfahan province. METHODS Among participants of Isfahan Cohort Study (ICS) by random sampling, 88 participants were selected and divided into case (with MetS) and control (without MetS) groups. A questionnaire including demographic data and CVD risk factors was completed for all of the participants. Physical examination and blood pressure, height, weight and waist circumference measurements were done for all subjects. Vascular echocardiography was done for evaluation of IMT of each carotid artery of both sides. Interlukin-6 (IL-6), interlukin-10 (IL-10), highly sensitive C-reactive protein (hs-CRP), ghrelin and adiponectin levels were measured using ELIZA method. Data were entered in SPSS15 software and analyzed by t-test, chi square, Pearson correlation and linear regression analyze. RESULTS The mean waist circumference, BMI, systolic blood pressure, diastolic blood pressure, hs-CRP and IMT of left carotid artery were significantly higher in participants with Mets. There was significant correlation between left carotid IMT and IL-6 level in all patients (P = 0.03). After adjustment for age and sex, significant relationship in groups with MetS was only reported between the left IMT and IL-6 (P = 0.02). There was no relation between IMT and other inflammatory markers in subjects with and without MetS. CONCLUSION Significant correlation between IL-6 and IMT was reported in patients with MetS. While no significant correlation between IL-10, adiponectin and ghrelin with IMT was observed in metabolic syndrome group. PMID:22577415

[Suspected Alzheimer's disease. Selection of outpatients for neuropsychological assessment].

PubMed

Wolf, S A; Henry, M; Deike, R; Ebert, A D; Wallesch, C-W

2008-04-01

Incipient Alzheimer's disease (AD) is frequently suspected by neurologists and psychiatrists, but diagnosis is difficult to establish. The aim of this report was to analyse to what extent suspicion is confirmed by a comprehensive neuropsychological examination intended to distinguish different types of dementia. Descriptive data analysis was used for investigating the differential diagnoses of 47 outpatients with suspected AD referred to a department of neuropsychology by physicians in private practice. Data analysis was based upon the NINCDS-ADRDA diagnostic criteria of AD. Only 38% of the outpatients examined with suspected AD met the NINCDS-ADRDA diagnostic criteria for AD or mixed dementia from a neuropsychological point of view, whereas 22% met criteria for other types of dementia. The remaining patients met criteria for distinct differential diagnoses (23%) or lacked pathological findings in neuropsychological functions (17%). Neuropsychology is an essential part in the differential diagnosis of mild to moderate dementias. It can aid in differential therapeutic considerations concerning the treatment of dementia, for example in selecting appropriate treatments or avoiding expensive but inappropriate ones.

Metabolic syndrome: pathogenesis, medical care and dental implications.

PubMed

Friedlander, Arthur H; Weinreb, Jane; Friedlander, Ida; Yagiela, John A

2007-02-01

The dental literature contains little information about metabolic syndrome (MetS) and its dental implications. The authors conducted a MEDLINE search for the period 2000 through 2005, using the term "metabolic syndrome" to define its pathophysiology, medical treatment and dental implications. MetS is the co-occurrence of abdominal obesity, hyper-triglyceridemia, reduced high-density lipoprotein cholesterol levels, hypertension and impaired fasting glucose, which results from consumption of a high-calorie diet and decreased levels of physical activity superimposed on the appropriate genetic setting. Components of MetS synergistically promote the development of atherosclerosis, resulting in myocardial infarction and stroke. Deteriorating oral health status is associated with worsening of the atherogenic profile. Tooth loss often results in chewing difficulties because of inadequate occlusive surfaces and may lead to alterations in food selection and dietary quality. This, in turn, adversely affects body composition and nutritional status, both of which are related to vascular health. Dentists should develop treatment plans that preserve and restore the dentition, thus ensuring maximum masticatory efficiency and affording patients the optimum opportunity to consume food that will not foster atherogenesis.

Is the Val66Met polymorphism of the brain-derived neurotrophic factor gene associated with panic disorder? A meta-analysis.

PubMed

Chen, Kaiyuan; Wang, Na; Zhang, Jie; Hong, Xiaohong; Xu, Haiyun; Zhao, Xiaofeng; Huang, Qingjun

2017-06-01

Although emerging evidence has suggested an association between the Val66Met (rs6265) polymorphisms in brain-derived neurotrophic factor (BDNF) gene and the panic disorder, the conclusion is inclusive given the mixed results. This meta-analysis reviewed and analyzed the recent studies addressing the potential association between the Val66Met polymorphisms and panic disorder susceptibility. Related case-control studies were retrieved by database searching and selected according to established inclusion criteria. Six articles were identified, which explored the association between the BDNF Val66Met polymorphism and panic disorder. Statistical analyses revealed no association for the allele contrast and the dominant model. However, the recessive model showed a significant association between the BDNF Val66Met polymorphism and panic disorder (odds ratio = 1.26, 95% confidence interval = 1.04-1.52, z = 2.39, P = 0.02). Despite of some limitations, this meta-analysis suggests that the Val66Met polymorphism of BDNF gene is a susceptibility factor for panic disorder. © 2015 Wiley Publishing Asia Pty Ltd.

A New Transgenic Mouse Model of Heart Failure and Cardiac Cachexia Raised by Sustained Activation of Met Tyrosine Kinase in the Heart.

PubMed

Sala, Valentina; Gatti, Stefano; Gallo, Simona; Medico, Enzo; Cantarella, Daniela; Cimino, James; Ponzetto, Antonio; Crepaldi, Tiziana

2016-01-01

Among other diseases characterized by the onset of cachexia, congestive heart failure takes a place of relevance, considering the high prevalence of this pathology in most European countries and in the United States, and is undergoing a rapid increase in developing countries. Actually, only few models of cardiac cachexia exist. Difficulties in the recruitment and follow-up of clinical trials implicate that new reproducible and well-characterized animal models are pivotal in developing therapeutic strategies for cachexia. We generated a new model of cardiac cachexia: a transgenic mouse expressing Tpr-Met receptor, the activated form of c-Met receptor of hepatocyte growth factor, specifically in the heart. We showed that the cardiac-specific induction of Tpr-Met raises a cardiac hypertrophic remodelling, which progresses into concentric hypertrophy with concomitant increase in Gdf15 mRNA levels. Hypertrophy progresses to congestive heart failure with preserved ejection fraction, characterized by reduced body weight gain and food intake and skeletal muscle wasting. Prevention trial by suppressing Tpr-Met showed that loss of body weight could be prevented. Skeletal muscle wasting was also associated with altered gene expression profiling. We propose transgenic Tpr-Met mice as a new model of cardiac cachexia, which will constitute a powerful tool to understand such complex pathology and test new drugs/approaches at the preclinical level.

Evaluation of Fatigue Crack Growth and Fracture Properties of Cryogenic Model Materials

NASA Technical Reports Server (NTRS)

Newman, John A.; Forth, Scott C.; Everett, Richard A., Jr.; Newman, James C., Jr.; Kimmel, William M.

2002-01-01

The criteria used to prevent failure of wind-tunnel models and support hardware were revised as part of a project to enhance the capabilities of cryogenic wind tunnel testing at NASA Langley Research Center. Specifically, damage-tolerance fatigue life prediction methods are now required for critical components, and material selection criteria are more general and based on laboratory test data. The suitability of two candidate model alloys (AerMet 100 and C-250 steel) was investigated by obtaining the fatigue crack growth and fracture data required for a damage-tolerance fatigue life analysis. Finally, an example is presented to illustrate the newly implemented damage tolerance analyses required of wind-tunnel model system components.

Prevalence of metabolic syndrome and its related factors among North Korean refugees in South Korea: a cross-sectional study.

PubMed

Kim, Yoon Jung; Lee, Yo Han; Lee, Yun Jeong; Kim, Kyeong Jin; An, Jee Hyun; Kim, Nam Hoon; Kim, Hee Young; Choi, Dong Seop; Kim, Sin Gon

2016-06-01

To determine the prevalence of metabolic syndrome (MetS) and its related factors among North Korean refugees (NKR) in South Korea. Cross-sectional study conducted using a questionnaire and anthropometric and biochemical data on NKR in South Korea. Seoul, South Korea. A sample of NKR who voluntarily underwent medical examinations in Anam Hospital of Korea University, Seoul, South Korea (N=708, consisting of 161 males and 547 females). To compare the prevalence of MetS, 1416 age- and gender-matched individuals from the South Korean population (SKP, at a ratio of 1:2 to NKR) were randomly selected from the fifth Korean National Health and Nutrition Examination Survey. The prevalence of MetS and its related factors among NKR in South Korea and comparison with its prevalence among the general SKP. The prevalence of MetS among male and female NKR in South Korea was 19.7% and 17.2%, respectively. Although obesity is more prevalent in South than in North Korea, we found no difference in the prevalence of MetS between the female NKR and SKP groups (17.2% vs 16.6%, respectively; p=0.830). As regards the males, the small sample size of the NKR group yielded insufficient evidence of any difference in MetS prevalence between the NKR and SKP groups (19.7% vs 26.2%, respectively; p=0.134). We found that excess weight gain (≥5%) in South Korea was significantly associated with MetS among NKR. The prevalence of MetS among NKR did not differ from that in the SKP group despite the lower prevalence of obesity in NKR than in the general SKP. The fact that excess weight gain in South Korea was associated with the risk of MetS suggests that public health policy makers should focus on preventing excess weight gain in NKR during resettlement in South Korea. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Age-dependent systemic DNA damage in early Type 2 Diabetes mellitus.

PubMed

Rogulj, Dinko; El Aklouk, Ismail; Konjevoda, Paško; Ljubić, Spomenka; Pibernik Okanović, Mirjana; Barbir, Ante; Luburić, Marijana; Radman, Maja; Budinski, Ninoslav; Vučić Lovrenčić, Marijana

2017-01-01

Oxidative stress, capable of eliciting damage to various biomolecules including DNA, is a recognized component of diabetes mellitus and its complications. Metabolic syndrome (MetS) is associated with the development of type 2 diabetes mellitus (T2DM), as well as other unfavorable outcomes. The aim of this study was to elucidate the role of oxidative stress in the development of T2DM, by investigating association of oxidative DNA damage with metabolic parameters in subjects with MetS and early T2DM. Selected anthropometric and biochemical parameters of MetS, inflammation and oxidative DNA damage: body mass index (BMI), fatty liver index (FLI), waist circumference (WC), total cholesterol, HDL and LDL-cholesterol, gamma-glutamyl transpeptidase (GGT), uric acid, C-reactive protein (CRP), total leukocyte/neutrophil count, and urinary 8-hidroxy-deoxyguanosine (u-8-OHdG) were assessed in male subjects with MetS and both younger (≤55 years) and older (>55 years) subjects with T2DM of short duration without complications. BMI, FLI, WC, total and LDL-cholesterol and uric acid were higher, while the u-8-OHdG was lower in MetS group, when compared to older T2DM subjects. None of these parameters were different neither between MetS and younger T2DM, nor between two sub-groups of subjects with T2DM. Values of CRP, HDL-cholesterol, triglycerides, GGT, leukocytes and neutrophils were not different between all examined groups of subjects. Higher 8-OHdG in older subjects with T2DM suggests that both aging process and diabetes could contribute to the development of DNA damage. Oxidative DNA damage cannot serve as an universal early marker of T2DM.

Metabolic syndrome: An independent risk factor for erectile dysfunction

PubMed Central

Sanjay, Saran; Bharti, Gupta Sona; Manish, Gutch; Rajeev, Philip; Pankaj, Agrawal; Puspalata, Agroiya; Keshavkumar, Gupta

2015-01-01

Objective: The objective was to determine the role of various components of metabolic syndrome (MetS) as independent risk factor for erectile dysfunction (ED). Materials and Methods: A total of 113 subjects of MetS, as recommended by recent IDF and AHA/NHLBI joint interim statement were selected for study who presented for ED. After doing Anthropometric examination, fasting laboratory assay for fasting plasma glucose (FPG), fasting insulin, hemoglobin A1c, triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and 2 h oral glucose tolerance test (OGTT) was done. Erectile function was assessed by completing questions one through five of the International Index of Erectile Function (IIEF-5). A multiple linear regression analysis was carried out on 66 subjects with IIEF-5 score as dependent variable and components of MetS FPG, 2 h OGTT, TG, HDL, and waist circumference as independent variables. Results: Using a multiple linear regression analysis, we observed that presence of the various components of MetS was associated with ED and a decrease IIEF-5 score and this effect was greater than the effect associated with any of the individual components. Of the individual components of the MetS, HDL (B = 0.136; P = 0.004) and FPG (B = −0.069; P = 0.007) conferred the strongest effect on IIEF-5 score. However, overall age had most significant effect on IIEF-5 score. Conclusion: It is crucial to formulate strategies and implement them to prevent or control the epidemic of the MetS and its consequences. The early identification and treatment of risk factors might be helpful to prevent ED and secondary cardiovascular disease, including diet and lifestyle interventions. PMID:25729692

Metabolic syndrome: An independent risk factor for erectile dysfunction.

PubMed

Sanjay, Saran; Bharti, Gupta Sona; Manish, Gutch; Rajeev, Philip; Pankaj, Agrawal; Puspalata, Agroiya; Keshavkumar, Gupta

2015-01-01

The objective was to determine the role of various components of metabolic syndrome (MetS) as independent risk factor for erectile dysfunction (ED). A total of 113 subjects of MetS, as recommended by recent IDF and AHA/NHLBI joint interim statement were selected for study who presented for ED. After doing Anthropometric examination, fasting laboratory assay for fasting plasma glucose (FPG), fasting insulin, hemoglobin A1c, triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and 2 h oral glucose tolerance test (OGTT) was done. Erectile function was assessed by completing questions one through five of the International Index of Erectile Function (IIEF-5). A multiple linear regression analysis was carried out on 66 subjects with IIEF-5 score as dependent variable and components of MetS FPG, 2 h OGTT, TG, HDL, and waist circumference as independent variables. Using a multiple linear regression analysis, we observed that presence of the various components of MetS was associated with ED and a decrease IIEF-5 score and this effect was greater than the effect associated with any of the individual components. Of the individual components of the MetS, HDL (B = 0.136; P = 0.004) and FPG (B = -0.069; P = 0.007) conferred the strongest effect on IIEF-5 score. However, overall age had most significant effect on IIEF-5 score. It is crucial to formulate strategies and implement them to prevent or control the epidemic of the MetS and its consequences. The early identification and treatment of risk factors might be helpful to prevent ED and secondary cardiovascular disease, including diet and lifestyle interventions.

Opposite effects of tamoxifen on metabolic syndrome-induced bladder and prostate alterations: a role for GPR30/GPER?

PubMed

Comeglio, P; Morelli, A; Cellai, I; Vignozzi, L; Sarchielli, E; Filippi, S; Maneschi, E; Corcetto, F; Corno, C; Gacci, M; Vannelli, G B; Maggi, M

2014-01-01

BPH and LUTS have been associated to obesity, hypogonadism, and metabolic syndrome (MetS). MetS-induced prostate and bladder alterations, including inflammation and tissue remodeling, have been related to a low-testosterone and high-estrogen milieu. In addition to ERs, GPR30/GPER is able to mediate several estrogenic non-genomic actions. Supplementing a subgroup of MetS rabbits with tamoxifen, we analyzed the in vivo effects on MetS-induced prostate and bladder alterations. The effects of selective ER/GPER ligands and GPER silencing on prostate inflammation were also studied in vitro using hBPH cells. ERα, ERβ, and PR expression was upregulated in MetS bladder, where tamoxifen decreased ERα and PR expression, further stimulating ERβ. In addition, tamoxifen-dosing decreased MetS-induced overexpression of inflammatory and tissue remodeling genes. In prostate, sex steroid receptors, pro-inflammatory and pro-fibrotic genes were upregulated in MetS. However, tamoxifen did not affect them and even increased COX-2. In hBPH cells, 17β-estradiol increased IL-8 secretion, an effect blunted by co-treatment with GPER antagonist G15 but not by ER antagonist ICI 182,780, which further increased it. GPER agonist G1 dose-dependently (IC50  = 1.6 nM) induced IL-8 secretion. In vitro analysis demonstrated that GPER silencing reverted these stimulatory effects. GPER can be considered the main mediator of estrogen action in prostate, whereas in bladder the mechanism appears to rely on ERα, as indicated by in vivo experiments with tamoxifen dosing. Limiting the effects of the MetS-induced estrogen action via GPER could offer new perspectives in the management of BPH/LUTS, whereas tamoxifen dosing showed potential benefits in bladder. © 2013 Wiley Periodicals, Inc.

Association Study between Ghrelin Gene Polymorphism and Metabolic Syndrome in a Han Chinese Population.

PubMed

You, Yueyue; Yu, Yaqin; Wu, Yanhua; Rao, Wenwang; Zhang, Yangyu; Liu, Yingyu; Yang, Guang; Fu, Yingli; Shi, Jieping; Kou, Changgui

2017-01-01

Ghrelin, in humans, is a hormone secreted from the stomach with an orexigenic effect, which is good for digestion and absorption, as well as regulating physical growth, metabolism, and energy balance. It is also involved in the development of metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM). This study assessed the association between single nucleotide variants of the GHRL gene and the risk of metabolic syndrome in a Han Chinese population. A case-control study was performed on 3780 Han Chinese comprising 1813 MetS cases and 1967 controls. Three missense polymorphisms in GHRL (rs26802, rs10490816, and rs696217) were selected, and the association between these polymorphisms and the risk of MetS was investigated. Metabolic syndrome was defined according to the criteria of the International Diabetes Federation (IDF). Using Pearson's 2 test, we found that there were no significant differences in genotype distributions and allele frequencies between cases and controls (all p > 0.05). There were also no significant differences in haplotype distributions between MetS cases and healthy controls. Furthermore, we confirmed that rs26802 of the GHRL gene is associated with body mass index (BMI), waist circumference, systolic blood pressure (SBP), and fasting glucose; rs10490816 is associated with triglycerides (TG) and total cholesterol (TC); while rs696217 is associated with hip circumference and fasting glucose. We concluded that mutations in the GHRL gene did not confer risk for MetS in our study population. Therefore, functional analysis and replication studies in other populations are needed to further investigate the exact role of the GHRL gene in MetS.

Distinct Involvement of the Gab1 and Grb2 Adaptor Proteins in Signal Transduction by the Related Receptor Tyrosine Kinases RON and MET

PubMed Central

Chaudhuri, Amitabha; Xie, Ming-Hong; Yang, Becky; Mahapatra, Kaushiki; Liu, Jinfeng; Marsters, Scot; Bodepudi, Sweta; Ashkenazi, Avi

2011-01-01

Although the signal transduction mechanisms of the receptor tyrosine kinase MET are well defined, less is known about its close relative RON. MET initiates intracellular signaling by autophosphorylation on specific cytoplasmic tyrosines that form docking sites for the adaptor proteins Grb2 and Gab1. Grb2 binds directly and is essential for all of the biological activities of MET. Gab1 docks either directly or indirectly via Grb2 and controls only a subset of MET functions. Because MET and RON possess similar adaptor binding sites, it was anticipated that their adaptor interactions would be conserved. Here we show that in contrast to MET, RON relies primarily on Gab1 for signal transmission. Surprisingly, disruption of the Grb2 docking site of RON or Grb2 depletion augments activity, whereas enhancement of Grb2 binding attenuates Gab1 recruitment and signaling. Hence, RON and MET differ in their adaptor interactions; furthermore, Grb2 performs a novel antagonistic role in the context of RON signaling. PMID:21784853

Predictive utility of blood pressure, waist circumference and body mass index for metabolic syndrome in patients with schizophrenia in Singapore.

PubMed

Nurjono, Milawaty; Lee, Jimmy

2013-05-01

This study aims to examine and compare the predictive utility of blood pressure (BP), waist circumference (WC) and body mass index (BMI), and to determine optimal cut-off values in prediction of metabolic syndrome (MetS) in patients with chronic schizophrenia. About 100 patients with chronic schizophrenia were recruited. BMI and BP were measured and laboratory tests to evaluate patients' high-density lipoprotein cholesterol, triglycerides and glucose levels were performed. Presence of MetS was examined according to AHA/NHLBI guidelines. Predictive utility of BP, WC and BMI was examined using receiver operating curve and discriminant indices were determined accordingly. Forty-six (46%) patients were identified to have MetS. BMI of ≥23 kg m(-2) was most accurate (AUC = 0.83, P < 0.001), with sensitivity of 93.5%, specificity of 48.1%, positive predictive value of 60.6% and negative predictive value of 92.9% in identifying MetS. This finding has immediate and significant clinical implications in the local population with schizophrenia. © 2012 Wiley Publishing Asia Pty Ltd.

Anthropometry and physical activity level in the prediction of metabolic syndrome in children.

PubMed

Andaki, Alynne Christian Ribeiro; Tinôco, Adelson Luiz Araújo; Mendes, Edmar Lacerda; Andaki Júnior, Roberto; Hills, Andrew P; Amorim, Paulo Roberto S

2014-10-01

To evaluate the effectiveness of anthropometric measures and physical activity level in the prediction of metabolic syndrome (MetS) in children. Cross-sectional study with children from public and private schools. Children underwent an anthropometric assessment, blood pressure measurement and biochemical evaluation of serum for determination of TAG, HDL-cholesterol and glucose. Physical activity level was calculated and number of steps per day obtained using a pedometer for seven consecutive days. Viçosa, south-eastern Brazil. Boys and girls (n 187), mean age 9·90 (SD 0·7) years. Conicity index, sum of four skinfolds, physical activity level and number of steps per day were accurate in predicting MetS in boys. Anthropometric indicators were accurate in predicting MetS for girls, specifically BMI, waist circumference measured at the narrowest point and at the level of the umbilicus, four skinfold thickness measures evaluated separately, the sum of subscapular and triceps skinfold thickness, the sum of four skinfolds and body fat percentage. The sum of four skinfolds was the most accurate method in predicting MetS in both genders.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barata-Vallejo, Sebastian; Ferreri, Carla; Zhang, Tao

Important biological consequences are related to the reaction of HO radicals with methionine (Met). Several fundamental aspects remain to be defined when Met is an amino acid residue incorporated in the interior of peptides and proteins. The present study focuses on Gly-Met-Gly, the simplest peptide where Met is not a terminal residue. The reactions of HO with Gly-Met-Gly and its N-acetyl derivative were studied by pulse radiolysis technique. The transient absorption spectra were resolved into contributions from specific components of radical intermediates. Moreover, a detailed product analysis is provided for the first time for Met-containing peptides in radiolytic studies tomore » support the mechanistic proposal. By parallel radiolytical and electrochemical reactions and consequent product identification, the formation of sulfoxide attributed to the direct HO radical attack on the sulfide functionality of the Met residue could be excluded, with the in situ generated hydrogen peroxide responsible for this oxidation. LC–MS and high resolution MS/MS were powerful analytical tools to envisage the structures of five products, thus allowing to complete the mechanistic picture of the overall Met-containing peptide reactivity.« less

Micro-Pressure Sensors for Future Mars Missions

NASA Technical Reports Server (NTRS)

Catling, David C.

1996-01-01

The joint research interchange effort was directed at the following principal areas: u further development of NASA-Ames' Mars Micro-meteorology mission concept as a viable NASA space mission especially with regard to the science and instrument specifications u interaction with the flight team from NASA's New Millennium 'Deep-Space 2' (DS-2) mission with regard to selection and design of micro-pressure sensors for Mars u further development of micro-pressure sensors suitable for Mars The research work undertaken in the course of the Joint Research Interchange should be placed in the context of an ongoing planetary exploration objective to characterize the climate system on Mars. In particular, a network of small probes globally-distributed on the surface of the planet has often been cited as the only way to address this particular science goal. A team from NASA Ames has proposed such a mission called the Micrometeorology mission, or 'Micro-met' for short. Surface pressure data are all that are required, in principle, to calculate the Martian atmospheric circulation, provided that simultaneous orbital measurements of the atmosphere are also obtained. Consequently, in the proposed Micro-met mission a large number of landers would measure barometric pressure at various locations around Mars, each equipped with a micro-pressure sensor. Much of the time on the JRI was therefore spent working with the engineers and scientists concerned with Micro-met to develop this particular mission concept into a more realistic proposition.

Dietary intake in midlife and associations with standard of living, education and nutrition literacy.

PubMed

Wall, Catherine L; Gearry, Richard B; Pearson, John; Parnell, Winsome; Skidmore, Paula M L

2014-07-04

Cardiovascular disease is a leading cause of death in New Zealand, but risk factors may be decreased by consuming a heart healthy diet. This pilot study investigated whether participants met the guidelines for a heart healthy diet and whether a novel heart healthy dietary pattern could be identified using principal components analysis (PCA). The second aim of this project was to assess if higher education, standard of living and nutrition literacy are associated with a heart healthy dietary pattern. This exploratory study was undertaken using data from the first participants enrolled in the Canterbury Health Ageing and Lifecourse study: an observational study of 50 year olds in the Canterbury District Health Board region. Eighty-two people were selected from the General and Maori electoral role and interviewed prior to the 22 February 2011 Christchurch Earthquake. PCA was conducted to identify dietary patterns, based on intake of specific nutrients as indicated by the New Zealand and international heart healthy dietary guidelines. 62 participants completed questionnaires and an estimated food record. No participants met all five of the heart healthy dietary guidelines. One dietary pattern was produced by PCA: a "higher CVD risk" pattern. Regression analysis indicated that higher standard of living, education and nutrition literacy were inversely associated with a "higher CVD risk" pattern. Higher standard of living, education and nutrition literacy were associated with a healthier dietary eating pattern. However, as no participants met all the dietary recommendations more education and support is needed to help people meet these.

[Molecular biology of renal cancer: bases for genetic directed therapy in advanced disease].

PubMed

Maroto Rey, José Pablo; Cillán Narvaez, Elena

2013-06-01

There has been expansion of therapeutic options in the management of metastatic renal cell carcinoma due to a better knowledge of the molecular biology of kidney cancers. There are different tumors grouped under the term renal cell carcinoma, being clear cell cancer the most frequent and accounting for 80% of kidney tumors. Mutations in the Von Hippel-Lindau gene can be identified in up to 80% of sporadic clear cell cancer, linking a genetically inheritable disease where vascular tumors are frequent, with renal cell cancer. Other histologic types present specific alterations in molecular pathways, like c-MET in papillary type I tumors, and Fumarase Hydratase in papillary type II tumors. Identification of the molecular alteration for a specific tumor may offer an opportunity for treatment selection based on biomarkers, and, in the future, for developing an engineering designed genetic treatment.

Contamination of planets by nonsterile flight hardware.

NASA Technical Reports Server (NTRS)

Wolfson, R. P.; Craven, C. W.

1971-01-01

The various factors about space missions and spacecraft involved in the study of nonsterile space flight hardware with respect to their effects on planetary quarantine are reviewed. It is shown that methodology currently exists to evaluate the various potential contamination sources and to take appropriate steps in the design of spacecraft ha rdware and mission parameters so that quarantine constraints are met. This work should be done for each program so that the latest knowledge pertaining to various biological questions is utilized, and so that the specific hardware designs of the program can be assessed. The general trend of specific recommendations include: (1) biasing the launch trajectory away from planet to assure against accidental impact of the spacecraft; (2) selecting planetary orbits that meet quarantine requirements - both for accidental impact and for minimizing contamination probabilities due to ejecta; and (3) manufacturing and handling spacecraft under cleanliness conditions assuring minimum bioload.

Chemotherapy-Induced Nausea and Vomiting Mitigation With Music Interventions
.

PubMed

Kiernan, Jason M; Conradi Stark, Jody; Vallerand, April H

2018-01-01

Despite three decades of studies examining music interventions as a mitigant of chemotherapy-induced nausea and vomiting (CINV), to date, no systematic review of this literature exists.
. PubMed, Scopus, PsycInfo®, CINAHL®, Cochrane Library, and Google Scholar were searched. Keywords for all databases were music, chemotherapy, and nausea.
. All studies were appraised for methodology and results.
. 10 studies met inclusion criteria for review. Sample sizes were generally small and nonrandomized. Locus of control for music selection was more often with the investigator rather than the participant. Few studies controlled for the emetogenicity of the chemotherapy administered, nor for known patient-specific risk factors for CINV.
. The existing data have been largely generated by nurse scientists, and implications for nursing practice are many, because music interventions are low-cost, easily accessible, and without known adverse effects. However, this specific body of knowledge requires additional substantive inquiry to generate clinically relevant data.

Guidelines as rationing tools: a qualitative analysis of psychosocial patient selection criteria for cardiac procedures

PubMed Central

Giacomini, Mita K.; Cook, Deborah J.; Streiner, David L.; Anand, Sonia S.

2001-01-01

Background Cardiac procedure guidelines often include psychosocial criteria for selecting patients that potentially introduce social value judgements into clinical decisions and decisions about the rationing of care. The aim of this study was to investigate the terms and justifications for and the meanings of psychosocial patient characteristics used in cardiac procedure guidelines. Methods We selected English-language guidelines published since 1990 and chapters in textbooks published since 1989. These guidelines amalgamated multiple sources of evidence and expertise and made recommendations regarding patient selection for specific procedures. A multidisciplinary team of physicians and social scientists extracted passages regarding psychosocial criteria and developed categories and conceptual relationships to describe and interpret their content. Results Sixty-five papers met the criteria for inclusion in the study. Forty-five (69%) mentioned psychosocial criteria as procedure indications or contraindications. The latter fell into several categories, including behavioural and psychological issues, relationships with significant others, financial resources, social roles and environmental circumstances. Interpretation Psychosocial characteristics are portrayed as having 2 roles in patient selection: as risk factors intrinsic to the candidate or as indicators of need for special intervention. Guidelines typically simply list psychosocial contraindications without clarifying their specific nature or providing any justification for their use. Psychosocial considerations can help in the evaluation of patients for cardiac procedures, but they become ethically controversial when used to restrict access. The use of psychosocial indications and contraindications could be improved by more precise descriptions of the psychosocial problem at issue, explanations regarding why the criterion matters and justification of the characteristic using a biological rationale or research evidence. PMID:11258209

Radiation chemical studies of Gly-Met-Gly in aqueous solution

DOE PAGES

Barata-Vallejo, Sebastian; Ferreri, Carla; Zhang, Tao; ...

2016-10-25

Important biological consequences are related to the reaction of HO radicals with methionine (Met). Several fundamental aspects remain to be defined when Met is an amino acid residue incorporated in the interior of peptides and proteins. The present study focuses on Gly-Met-Gly, the simplest peptide where Met is not a terminal residue. The reactions of HO with Gly-Met-Gly and its N-acetyl derivative were studied by pulse radiolysis technique. The transient absorption spectra were resolved into contributions from specific components of radical intermediates. Moreover, a detailed product analysis is provided for the first time for Met-containing peptides in radiolytic studies tomore » support the mechanistic proposal. By parallel radiolytical and electrochemical reactions and consequent product identification, the formation of sulfoxide attributed to the direct HO radical attack on the sulfide functionality of the Met residue could be excluded, with the in situ generated hydrogen peroxide responsible for this oxidation. LC–MS and high resolution MS/MS were powerful analytical tools to envisage the structures of five products, thus allowing to complete the mechanistic picture of the overall Met-containing peptide reactivity.« less

Effects of the BDNF Val66Met polymorphism and met allele load on declarative memory related neural networks.

PubMed

Dodds, Chris M; Henson, Richard N; Suckling, John; Miskowiak, Kamilla W; Ooi, Cinly; Tait, Roger; Soltesz, Fruzsina; Lawrence, Phil; Bentley, Graham; Maltby, Kay; Skeggs, Andrew; Miller, Sam R; McHugh, Simon; Bullmore, Edward T; Nathan, Pradeep J

2013-01-01

It has been suggested that the BDNF Val66Met polymorphism modulates episodic memory performance via effects on hippocampal neural circuitry. However, fMRI studies have yielded inconsistent results in this respect. Moreover, very few studies have examined the effect of met allele load on activation of memory circuitry. In the present study, we carried out a comprehensive analysis of the effects of the BDNF polymorphism on brain responses during episodic memory encoding and retrieval, including an investigation of the effect of met allele load on memory related activation in the medial temporal lobe. In contrast to previous studies, we found no evidence for an effect of BDNF genotype or met load during episodic memory encoding. Met allele carriers showed increased activation during successful retrieval in right hippocampus but this was contrast-specific and unaffected by met allele load. These results suggest that the BDNF Val66Met polymorphism does not, as previously claimed, exert an observable effect on neural systems underlying encoding of new information into episodic memory but may exert a subtle effect on the efficiency with which such information can be retrieved.

Accuracy criteria voltage electrocardiography left ventricular hypertrophy to distinguish types of left ventricular hypertrophy geometry

NASA Astrophysics Data System (ADS)

Tumbur, O.; Safri, Z.; Hassan, R.

2018-03-01

Different types of left ventricular hypertrophy geometry are associated with different risk of cardiovascular disease. The purpose of this study was to determine the role of various ECG voltages of LVH to distinguish the type of LVH geometry. A cross-sectional study from June to November 2015, 100 patients in Adam Malik Hospital Medan. The result of LVH ECG criteria of Sokolow-Lyon was not met then obtained normal left ventricular geometry with 60% sensitivity, 72.22% specificity, and 71% accuracy. The eccentric type of LVH is obtained when the Cornel Voltage is not met; the sensitivity is 25%, specificity 71.88%, and 55% accuracy. Concentric geometric hypertrophy when the RV6/V5> 1 ratio is satisfied, the sensitivity is 55.56%, specificity 56.36%, and 56% accuracy. The RV6/V5>1 ratio was not met, the concentric geometry type of hypertrophy remodeling was determined with a sensitivity of 55.56%, specificity 49.45%, and 50% accuracy. Conclusions, various LVHECG criteria distinguish the type of LVH geometry. Sokolow-Lyon and Cornel Voltage sensitivity and specificity are better than the RV6/V5 ratio.

Impact of Helicobacter pylori Immunoglobulin G Levels and Atrophic Gastritis Status on Risk of Metabolic Syndrome.

PubMed

Takeoka, Atsushi; Tayama, Jun; Yamasaki, Hironori; Kobayashi, Masakazu; Ogawa, Sayaka; Saigo, Tatsuo; Hayashida, Masaki; Shirabe, Susumu

2016-01-01

Helicobacter pylori (HP) infection is implicated in gastric and extra-gastric diseases. While gastritis-related chronic inflammation represents a known trigger of metabolic disturbances, whether metabolic syndrome (MetS) is affected by gastritis status remains unclear. We aimed to clarify the effect of HP-related gastritis on the risk of MetS. We retrospectively enrolled patients undergoing screening for MetS between 2014 and 2015. Investigations included HP-specific immunoglobulin G (IgG) antibody assays to detect HP infection, and serum pepsinogen assays to evaluate atrophic gastritis status. The risk of MetS was evaluated via multiple logistic regression analyses with two covariates: serum HP infection status (IgG levels) and atrophic gastritis status (two criteria were applied; pepsinogen I/II ratio < 3 or both pepsinogen I levels ≤ 70 μg/L and pepsinogen I/II ratio < 3). Of 1,044 participants, 247 (23.7%) were HP seropositive, and 62 (6.0%) had MetS. HP seronegative and seropositive patients had similar risks of MetS. On the other hand, AG (defined in terms of serum PG I/II <3) was significant risk of MetS (OR of 2.52 [95% CI 1.05-7.52]). After stratification according to HP IgG concentration, patients with low HP infection status had the lowest MetS risk (defined as an odds ratio [OR] adjusted for age, sex, smoking, drinking and physical activity status). Taking this result as a reference, patients with negative, moderate, and high HP infection status had ORs (with 95% confidence intervals [CI]) of 2.15 (1.06-4.16), 3.69 (1.12-16.7), and 4.05 (1.05-26.8). HP-associated gastritis represents a risk factor for MetS. Research should determine why low and not negative HP infection status is associated with the lowest MetS risk.

Impact of Helicobacter pylori Immunoglobulin G Levels and Atrophic Gastritis Status on Risk of Metabolic Syndrome

PubMed Central

Takeoka, Atsushi; Tayama, Jun; Yamasaki, Hironori; Kobayashi, Masakazu; Ogawa, Sayaka; Saigo, Tatsuo; Hayashida, Masaki; Shirabe, Susumu

2016-01-01

Background Helicobacter pylori (HP) infection is implicated in gastric and extra-gastric diseases. While gastritis-related chronic inflammation represents a known trigger of metabolic disturbances, whether metabolic syndrome (MetS) is affected by gastritis status remains unclear. We aimed to clarify the effect of HP-related gastritis on the risk of MetS. Materials and Methods We retrospectively enrolled patients undergoing screening for MetS between 2014 and 2015. Investigations included HP-specific immunoglobulin G (IgG) antibody assays to detect HP infection, and serum pepsinogen assays to evaluate atrophic gastritis status. The risk of MetS was evaluated via multiple logistic regression analyses with two covariates: serum HP infection status (IgG levels) and atrophic gastritis status (two criteria were applied; pepsinogen I/II ratio < 3 or both pepsinogen I levels ≤ 70 μg/L and pepsinogen I/II ratio < 3). Results Of 1,044 participants, 247 (23.7%) were HP seropositive, and 62 (6.0%) had MetS. HP seronegative and seropositive patients had similar risks of MetS. On the other hand, AG (defined in terms of serum PG I/II <3) was significant risk of MetS (OR of 2.52 [95% CI 1.05–7.52]). After stratification according to HP IgG concentration, patients with low HP infection status had the lowest MetS risk (defined as an odds ratio [OR] adjusted for age, sex, smoking, drinking and physical activity status). Taking this result as a reference, patients with negative, moderate, and high HP infection status had ORs (with 95% confidence intervals [CI]) of 2.15 (1.06–4.16), 3.69 (1.12–16.7), and 4.05 (1.05–26.8). Conclusions HP-associated gastritis represents a risk factor for MetS. Research should determine why low and not negative HP infection status is associated with the lowest MetS risk. PMID:27851820

Histidine-rich stabilized polyplexes for cMet-directed tumor-targeted gene transfer

NASA Astrophysics Data System (ADS)

Kos, Petra; Lächelt, Ulrich; Herrmann, Annika; Mickler, Frauke Martina; Döblinger, Markus; He, Dongsheng; Krhač Levačić, Ana; Morys, Stephan; Bräuchle, Christoph; Wagner, Ernst

2015-03-01

Overexpression of the hepatocyte growth factor receptor/c-Met proto oncogene on the surface of a variety of tumor cells gives an opportunity to specifically target cancerous tissues. Herein, we report the first use of c-Met as receptor for non-viral tumor-targeted gene delivery. Sequence-defined oligomers comprising the c-Met binding peptide ligand cMBP2 for targeting, a monodisperse polyethylene glycol (PEG) for polyplex surface shielding, and various cationic (oligoethanamino) amide cores containing terminal cysteines for redox-sensitive polyplex stabilization, were assembled by solid-phase supported syntheses. The resulting oligomers exhibited a greatly enhanced cellular uptake and gene transfer over non-targeted control sequences, confirming the efficacy and target-specificity of the formed polyplexes. Implementation of endosomal escape-promoting histidines in the cationic core was required for gene expression without additional endosomolytic agent. The histidine-enriched polyplexes demonstrated stability in serum as well as receptor-specific gene transfer in vivo upon intratumoral injection. The co-formulation with an analogous PEG-free cationic oligomer led to a further compaction of pDNA polyplexes with an obvious change of shape as demonstrated by transmission electron microscopy. Such compaction was critically required for efficient intravenous gene delivery which resulted in greatly enhanced, cMBP2 ligand-dependent gene expression in the distant tumor.Overexpression of the hepatocyte growth factor receptor/c-Met proto oncogene on the surface of a variety of tumor cells gives an opportunity to specifically target cancerous tissues. Herein, we report the first use of c-Met as receptor for non-viral tumor-targeted gene delivery. Sequence-defined oligomers comprising the c-Met binding peptide ligand cMBP2 for targeting, a monodisperse polyethylene glycol (PEG) for polyplex surface shielding, and various cationic (oligoethanamino) amide cores containing terminal cysteines for redox-sensitive polyplex stabilization, were assembled by solid-phase supported syntheses. The resulting oligomers exhibited a greatly enhanced cellular uptake and gene transfer over non-targeted control sequences, confirming the efficacy and target-specificity of the formed polyplexes. Implementation of endosomal escape-promoting histidines in the cationic core was required for gene expression without additional endosomolytic agent. The histidine-enriched polyplexes demonstrated stability in serum as well as receptor-specific gene transfer in vivo upon intratumoral injection. The co-formulation with an analogous PEG-free cationic oligomer led to a further compaction of pDNA polyplexes with an obvious change of shape as demonstrated by transmission electron microscopy. Such compaction was critically required for efficient intravenous gene delivery which resulted in greatly enhanced, cMBP2 ligand-dependent gene expression in the distant tumor. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr06556e

Measuring quality of life among people living with HIV: a systematic review of reviews.

PubMed

Cooper, Vanessa; Clatworthy, Jane; Harding, Richard; Whetham, Jennifer

2017-11-15

A systematic review of reviews was conducted to identify and appraise brief measures of health-related quality of life (HRQoL) that have been used in peer-reviewed research with people living with HIV. The review was conducted in two stages: 1) search of electronic databases to identify systematic reviews of tools used to measure HRQoL in adults living with HIV, published since the year 2000; 2) selection of HRQol scales from those identified in the reviews. Inclusion criteria included scales that could be self-administered in 10 min or less, covering at least 3 domains of quality of life (physical function, social/role function and mental/emotional function). For generic scales, inclusion criteria included the availability of normative data while for HIV-specific scales, patient input into the development of the scale was required. Ten reviews met the inclusion criteria. Nine generic scales met the inclusion criteria: the EuroQol five dimensions questionnaire (EQ-5D); Health Utilities Index; McGill Quality of Life questionnaire; Medical Outcomes Study (MOS) Short Form (SF)-12; SF-36; World Health Organisation Quality of Life (WHOQOL- BREF), Questions of Life Satisfaction (FLZM) and SF-20. Available psychometric data supported the EQ-5D and SF-36. Seven HIV-specific scales met the inclusion criteria: the AIDS Clinical Trials Group (ACTG)-21; HIV-QL-31; MOS-HIV; Multidimensional Quality of Life Questionnaire for Persons with HIV/AIDS (MQOL-HIV), PROQOL-HIV, Symptom Quality of Life Adherence (HIV-SQUAD) and the WHOQOL-HIV BREF. Of the HIV -specific measures, the MOS-HIV was considered to have the most well-established psychometric properties, however limitations identified in the reviews included insufficient input from people living with HIV in the development of the scale, cross-cultural relevance and continued applicability. Two relatively new measures, the WHOQOL-HIV BREF and PROQOL-HIV, were considered to have promising psychometric properties and may have more relevance to people living with HIV. The findings highlight the need for further validation of HRQoL measures in people living with HIV. The choice of one measure over another is likely to be influenced by the purpose of the quality of life assessment and the domains of HRQoL that are most relevant to the specific research or clinical question.

Relation of Osteoprotegerin, Visfatin and Ghrelin to Metabolic Syndrome in Type 2 Diabetic Patients

PubMed Central

Ahmed, Manal Basyouni; Ismail, Maha Imam Ahmed; Meki, Abdel-Raheim M.

2015-01-01

Background It is now realized that insulin resistance plays a principal role in initiating the pathologic manifestations of the metabolic syndrome (MetS). Objectives The aim of this study was to assess the possible role of osteoprotegerin, visfatin and ghrelin in the pathogenesis of MetS among type 2 diabetes mellitus (T2DM). Design and methods Serum blood samples were obtained from 116 subjects (39 T2DM; 48 T2DM with MetS; 29 healthy controls). Glycemic status and lipid profile were assessed by enzymatic method. Osteoprotegerin, visfatin, ghrelin and insulin were measured by ELISA method. Results Osteoprotegerin and visfatin were significantly higher, while ghrelin was significantly lower in diabetic patients compared to healthy control group (p<0.05). Moreover, Osteoprotegerin and visfatin showed significant higher levels in T2DM patients with MetS than those without MetS (p<0.05). The best cut-off values for the investigated markers were determined by ROC curve. Osteoprotegerin (1.06 ng/mL), visfatin (32.27 ng/mL) and ghrelin (33.65 pg/mL) presented sensitivity of 76%, 92% and 39.1%; respectively and specificity of 41%, 69.2% and 62.9%; respectively, in predicting MetS among T2DM. Among the investigated parameters, Visfatin was the one which predicts MetS among diabetic patients [AUC=0.88, p<0.05]. Conclusion Osteoprotegerin, visfatin and ghrelin might be implicated in the pathogenesis of diabetes. Moreover, osteoprotegerin and visfatin may have additional potential role in the development of the metabolic syndrome. Visfatin was superior among studied parameters in predicting MetS among T2DM. PMID:26309431

Percentage of Body Fat and Fat Mass Index as a Screening Tool for Metabolic Syndrome Prediction in Colombian University Students.

PubMed

Ramírez-Vélez, Robinson; Correa-Bautista, Jorge Enrique; Sanders-Tordecilla, Alejandra; Ojeda-Pardo, Mónica Liliana; Cobo-Mejía, Elisa Andrea; Castellanos-Vega, Rocío Del Pilar; García-Hermoso, Antonio; González-Jiménez, Emilio; Schmidt-RioValle, Jacqueline; González-Ruíz, Katherine

2017-09-13

High body fat is related to metabolic syndrome (MetS) in all ethnic groups. Based on the International Diabetes Federation (IDF) definition of MetS, the aim of this study was to explore thresholds of body fat percentage (BF%) and fat mass index (FMI) for the prediction of MetS among Colombian University students. A cross-sectional study was conducted on 1687 volunteers (63.4% women, mean age = 20.6 years). Weight, waist circumference, serum lipids indices, blood pressure, and fasting plasma glucose were measured. Body composition was measured by bioelectrical impedance analysis (BIA) and FMI was calculated. MetS was defined as including more than or equal to three of the metabolic abnormalities according to the IDF definition. Receiver operating curve (ROC) analysis was used to determine optimal cut-off points for BF% and FMI in relation to the area under the curve (AUC), sensitivity, and specificity in both sexes. The overall prevalence of MetS was found to be 7.7%, higher in men than women (11.1% vs. 5.3%; p < 0.001). BF% and FMI were positively correlated to MetS components ( p < 0.05). ROC analysis indicated that BF% and FMI can be used with moderate accuracy to identify MetS in university-aged students. BF% and FMI thresholds of 25.55% and 6.97 kg/m² in men, and 38.95% and 11.86 kg/m² in women, were found to be indicative of high MetS risk. Based on the IDF criteria, both indexes' thresholds seem to be good tools to identify university students with unfavorable metabolic profiles.

Cut points of muscle strength associated with metabolic syndrome in men.

PubMed

Sénéchal, Martin; McGavock, Jonathan M; Church, Timothy S; Lee, Duck-Chul; Earnest, Conrad P; Sui, Xuemei; Blair, Steven N

2014-08-01

The loss of muscle strength with age increases the likelihood of chronic conditions, including metabolic syndrome (MetS). However, the minimal threshold of muscle strength at which the risk for MetS increases has never been established. This study aimed to identify a threshold of muscle strength associated with MetS in men. We created receiver operating curves for muscle strength and the risk of MetS from a cross-sectional sample of 5685 men age <50 yr and 1541 men age ≥50 yr enrolled in the Aerobics Center Longitudinal Study. The primary outcome measure, the MetS, was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria. Upper and lower body muscle strength was treated as a composite measure of one-repetition maximum tests on bench and leg press and scaled to body weight. Low muscle strength was defined as the lowest age-specific 20th percentile, whereas high muscle strength was defined as composite muscle strength above the 20th percentile. In men aged <50 yr, the odds of MetS were 2.20-fold (95% confidence interval = 1.89-2.54) higher in those with low muscle strength, independent of age, smoking, and alcohol intake. The strength of this association was similar for men age ≥50 yr (odds ratio = 2.11, 95% confidence interval = 1.62-2.74). In men age < 50 yr, the composite strength threshold associated with MetS was 2.57 kg·kg body weight, whereas in men age ≥ 50 yr the threshold was 2.35 kg·kg body weight. This study is the first to identify a threshold of muscle strength associated with an increased likelihood of MetS in men. Measures of muscle strength may help identify men at risk of chronic disease.

Sex differences in the association of phospholipids with components of the metabolic syndrome in young adults.

PubMed

Rauschert, Sebastian; Uhl, Olaf; Koletzko, Berthold; Mori, Trevor A; Beilin, Lawrence J; Oddy, Wendy H; Hellmuth, Christian

2017-01-01

There are differences in the prevalence and severity of diseases between males, females not taking hormonal contraceptives (non-HC females) and females taking hormonal contraceptives (HC females). The aim of this study was to identify sex-specific differences in the metabolome and its relation to components of the metabolic syndrome in a young adult population. The subjects analysed are from the 20-year follow-up of the Western Australian Pregnancy Cohort (Raine) Study. Two hundred fifteen plasma metabolites were analysed in 1021 fasted plasma samples by a targeted liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) metabolomics approach. Principal component analysis between males ( n  = 550), non-HC females ( n  = 199) and HC females ( n  = 269) was applied. Regression analysis with a sex × metabolite concentration interaction was performed on components of the MetS, namely waist circumference, systolic blood pressure, and plasma HDL-C, triglycerides and glucose concentration, as outcome to select the significant metabolites of the interaction. Those selected metabolites were used as predictors in a sex group stratified analysis to compare the different β coefficients and therefore the sex group-dependent associations. Principal component analysis between males, non-HC females, and HC females showed a general discriminating trend between males and HC females. One hundred twenty-seven metabolites were significantly different between males and non-HC females, whereas 97 differed between non-HC females and HC females. Males and non-HC females mainly differed in sphingomyelin, lyso-phosphatidylcholine, acyl-carnitine and amino acid species, whilst non-HC females and HC females mainly differed in phosphatidylcholine, lyso-phosphatidylcholine and acyl-carnitine concentrations. Forty-one metabolites (phosphatidylcholines, sphingomyelines, lyso-phosphatidylcholine) were significantly differently associated with the MetS factors in the different groups. We have shown clear differences between plasma metabolite concentrations in males, and HC or non-HC females, especially in lyso-phosphatidylcholine, sphingomyelin and phosphatidylcholine, which have been shown to associate with obesity in other studies. The association of these metabolites differed between sexes with components of the metabolic syndrome, which means that development of diseases like obesity and diabetes may differ between the sexes. Our findings highlight the importance of considering sex differences when conducting a metabolomics study and the need to account for the effect of HC usage in females in future studies.

Duodenal L cell density correlates with features of metabolic syndrome and plasma metabolites.

PubMed

van Baar, Annieke C G; Prodan, Andrei; Wahlgren, Camilla D; Poulsen, Steen S; Knop, Filip K; Groen, Albert K; Bergman, Jacques J; Nieuwdorp, Max; Levin, Evgeni

2018-05-01

Enteroendocrine cells are essential for the regulation of glucose metabolism, but it is unknown whether they are associated with clinical features of metabolic syndrome (MetS) and fasting plasma metabolites. We aimed to identify fasting plasma metabolites that associate with duodenal L cell, K cell and delta cell densities in subjects with MetS with ranging levels of insulin resistance. In this cross-sectional study, we evaluated L, K and delta cell density in duodenal biopsies from treatment-naïve males with MetS using machine-learning methodology. We identified specific clinical biomarkers and plasma metabolites associated with L cell and delta cell density. L cell density was associated with increased plasma metabolite levels including symmetrical dimethylarginine, 3-aminoisobutyric acid, kynurenine and glycine. In turn, these L cell-linked fasting plasma metabolites correlated with clinical features of MetS. Our results indicate a link between duodenal L cells, plasma metabolites and clinical characteristics of MetS. We conclude that duodenal L cells associate with plasma metabolites that have been implicated in human glucose metabolism homeostasis. Disentangling the causal relation between L cells and these metabolites might help to improve the (small intestinal-driven) pathophysiology behind insulin resistance in human obesity. © 2018 The authors.

Tumor Inhibitory Effect of IRCR201, a Novel Cross-Reactive c-Met Antibody Targeting the PSI Domain.

PubMed

Park, Hyunkyu; Kim, Donggeon; Kim, Eunmi; Sa, Jason K; Lee, Hee Won; Yu, Suji; Oh, Jiwon; Kim, Seok-Hyung; Yoon, Yeup; Nam, Do-Hyun

2017-09-13

Hepatocyte growth factor receptor (HGFR, c-Met) is an essential member of the receptor tyrosine kinase (RTK) family that is often dysregulated during tumor progression, driving a malignant phenotypic state and modulating important cellular functions including tumor growth, invasion, metastasis, and angiogenesis, providing a strong rationale for targeting HGF/c-Met signaling axis in cancer therapy. Based on its protumorigenic potentials, we developed IRCR201, a potent antagonistic antibody targeting the plexin-semaphorin-integrin (PSI) domain of c-Met, using synthetic human antibody phage libraries. We characterized and evaluated the biochemical properties and tumor inhibitory effect of IRCR201 in vitro and in vivo. IRCR201 is a novel fully-human bivalent therapeutic antibody that exhibits cross-reactivity against both human and mouse c-Met proteins with high affinity and specificity. IRCR201 displayed low agonist activity and rapidly depleted total c-Met protein via the lysosomal degradation pathway, inhibiting c-Met-dependent downstream activation and attenuating cellular proliferation in various c-Met-expressing cancer cells. In vivo tumor xenograft models also demonstrated the superior tumor inhibitory responsiveness of IRCR201. Taken together, IRCR201 provides a promising therapeutic agent for c-Met-positive cancer patients through suppressing the c-Met signaling pathway and tumor growth.

Structure of a microsporidian methionine aminopeptidase type 2 complexed with fumagillin and TNP-470

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alvarado, J.; Nemkal, A; Sauder, J

2009-01-01

Microsporidia are protists that have been reported to cause infections in both vertebrates and invertebrates. They have emerged as human pathogens particularly in patients that are immunosuppressed and cases of gastrointestinal infection, encephalitis, keratitis, sinusitis, myositis and disseminated infection are well described in the literature. While benzimidazoles are active against many species of microsporidia, these drugs do not have significant activity against Enterocytozoon bieneusi. Fumagillin and its analogues have been demonstrated to have activity in vitro and in animal models of microsporidiosis and human infections due to E. bieneusi. Fumagillin and its analogues inhibit methionine aminopeptidase type 2. Encephalitozoon cuniculimore » MetAP2 (EcMetAP2) was cloned and expressed as an active enzyme using a baculovirus system. The crystal structure of EcMetAP2 was determined with and without the bound inhibitors fumagillin and TNP-470. This structure classifies EcMetAP2 as a member of the MetAP2c family. The EcMetAP2 structure was used to generate a homology model of the E. bieneusi MetAP2. Comparison of microsporidian MetAP2 structures with human MetAP2 provides insights into the design of inhibitors that might exhibit specificity for microsporidian MetAP2.« less

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism affects sympathetic tone in a gender-specific way.

PubMed

Chang, Chuan-Chia; Chang, Hsin-An; Chen, Tien-Yu; Fang, Wen-Hui; Huang, San-Yuan

2014-09-01

The Val/Val genotype of the brain-derived neurotrophic factor (BDNF) polymorphism (Val66Met) has been reported to affect human anxiety-related phenotypes. Substantial research has demonstrated that anxiety is associated with sympathetic activation, while sex steroid hormones have been shown to exert differential actions in regulating BDNF expression. Thus, we examined whether the BDNF variant modulates autonomic function in a gender-dependent manner. From 708 adults initially screened for medical and psychiatric illnesses, a final cohort of 583 drug-free healthy Han Chinese (355 males, 228 females; age 34.43±8.42 years) was recruited for BDNF genotyping (Val/Val: 136, 23.3%, Val/Met: 294, 50.4%, and Met/Met: 153, 26.2%). Time- and frequency-domain analyses of heart rate variability (HRV) were used to assess autonomic outflow to the heart. Significant genotype-by-gender interaction effects were found on HRV indices. Even after adjusting for possible confounders, male participants bearing the Val/Val genotype had significant increases in low frequency (LF), LF% and LF/high frequency (HF) ratio, indicating altered sympathovagal balance with increased sympathetic modulation, compared to male Met/Met homozygotes. Females, however, showed an opposite but non-significant pattern. These results suggest that the studied BDNF polymorphism is associated with sympathetic control in a gender-specific way. The findings here support the view that male subjects with the Val/Val genotype have increased risk of anxiety by association with sympathetic activation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Analysis of the association of leptin and adiponectin concentrations with metabolic syndrome in children: Results from the IDEFICS study.

PubMed

Nappo, A; González-Gil, E M; Ahrens, W; Bammann, K; Michels, N; Moreno, L A; Kourides, Y; Iacoviello, L; Mårild, S; Fraterman, A; Molnàr, D; Veidebaum, T; Siani, A; Russo, P

2017-06-01

Adipokines may play a role in the pathogenesis of the metabolic syndrome (MetS) in children. We aimed to evaluate the association of leptin, adiponectin, and its ratio (L/A ratio) with the metabolic syndrome (MetS) in a subsample of the IDEFICS (Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS) cohort. Leptin, adiponectin and MetS parameters were measured in a subsample of 1253 children (3-9.9 years) participating to the IDEFICS study, grouped as: Non-OW (underweight/normal weight) and OW/Ob (overweight/obese). MetS was defined using the sex- and age-specific cut-offs based on the distribution of MetS components in the IDEFICS cohort. The prevalence of the MetS among OW/Ob was 24.8% and 27.1% in boys and girls respectively, whereas ≤2% among Non-OW. OW/Ob had significantly higher leptin and L/A ratio as compared to Non-OW. Significantly higher leptin was found in OW/Ob with MetS as compared with OW/Ob without MetS. Significantly lower adiponectin was observed only in OW/Ob girls as compared to Non-OW. A 1SD increase in leptin and L/A ratio z-scores or a 1SD decrease in adiponectin z-score were significantly associated with higher risk of MetS. After adjustment for BMI or body fat mass (BFM) the association remained significant only for leptin. We showed that in European children, higher leptin concentration is associated with MetS, even after adjusting for BMI or BFM, confirming an early role of leptin in MetS, while the association of adiponectin with MetS seems be mediated by body fat in this age range. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Childhood Age and Associations Between Childhood Metabolic Syndrome and Adult Risk for Metabolic Syndrome, Type 2 Diabetes Mellitus and Carotid Intima Media Thickness: The International Childhood Cardiovascular Cohort Consortium.

PubMed

Koskinen, Juha; Magnussen, Costan G; Sinaiko, Alan; Woo, Jessica; Urbina, Elaine; Jacobs, David R; Steinberger, Julia; Prineas, Ronald; Sabin, Matthew A; Burns, Trudy; Berenson, Gerald; Bazzano, Lydia; Venn, Alison; Viikari, Jorma S A; Hutri-Kähönen, Nina; Raitakari, Olli; Dwyer, Terence; Juonala, Markus

2017-08-16

There is paucity of knowledge concerning the specific age in youth when the associations of metabolic syndrome (MetS) begin to be operative. Thus, we investigated the relation of age to the associations of childhood MetS with adult MetS, type 2 diabetes mellitus and high carotid intima-media thickness. Five thousand eight-hundred three participants were analyzed in 4 cohort studies (Cardiovascular Risk in Young Finns, Bogalusa Heart Study, Princeton Lipid Research Study, Insulin Study). International cutoffs and previously used 75th percentile cutoffs were used for children to define MetS and its components. Mean follow-up period was 22.3 years. Logistic regression was used to calculate risk ratios and 95% confidence intervals. Childhood MetS and overweight were associated with over 2.4-fold risk for adult MetS from the age of 5 years onward. Risk for type 2 diabetes mellitus was increased from the age of 8 (risk ratio, 2.6-4.1; 95% confidence interval, 1.35-6.76 and 1.12-7.24, respectively) onward for the 2 childhood MetS criteria based on international cut-off values and for childhood overweight. Risk for high carotid intima-media thickness was significant at ages 11 to 18 years in relation to childhood MetS or overweight (risk ratio, 2.44-4.22; 95% confidence interval, 1.55-3.55 and 2.55-5.66, respectively). Continuous childhood MetS score was associated with adult MetS from the age of 5, with type 2 diabetes mellitus from the age of 14 and with high carotid intima-media thickness from the age of 11 years onward. Adult MetS was predicted by MetS in childhood beginning at age 5. However, adult type 2 diabetes mellitus and subclinical atherosclerosis were not predicted by childhood data until after age 8. Body mass index measurement alone at the same age points provided similar findings. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Metallocarbohedrenes: Transmission Electron Microscopy of Mass Gated Deposits

NASA Astrophysics Data System (ADS)

Castleman, M. E. Lyn, Jr.

2002-03-01

Titanium and zirconium Met-Car cluster ions have been detected from the direct laser vaporization of metal-graphite mixtures using time-of-flight mass spectrometry. Optimization of the production conditions enabled sufficient intensities to mass select and deposit Met-Cars on surfaces. High-resolution transmission electron microscopy images of mass gated Met-Car species reveals deposited nanocrystals 2 nm in diameter. Diffraction patterns indicate the presence of multiple species and shows that the deposits have spatial orientation. Lattice parameters have been extracted. The implication of the findings will be discussed. Support for the work has been from the AFOSR F49620-01-1-0122.

The MMP-9 -1562 C/T Polymorphism in the Presence of Metabolic Syndrome Increases the Risk of Clinical Events in Patients with Coronary Artery Disease

PubMed Central

Opstad, Trine B.; Arnesen, Harald; Pettersen, Alf Å.; Seljeflot, Ingebjørg

2014-01-01

Background and Objectives Elevated levels of matrix metalloproteinase (MMP)-9 have been associated with the metabolic syndrome (MetS) and cardiovascular events. The MMP-9 −1562 C/T polymorphism has furthermore been shown as a risk factor for coronary artery disease (CAD). The non-favourable cardiometabolic state in MetS may increase the risk. We aimed to investigate the influence of MMP-9 −1562 C/T polymorphism in subjects with CAD and MetS. Methods Patients (n = 1000) with verified CAD stratified in Mets +/− (n = 244/756), were analyzed for the MMP-9 −1562 C/T polymorphism and related to clinical events after 2 years follow-up. Serum levels of total MMP-9 and tissue inhibitor of matrix metalloproteinases (TIMP)-1were analyzed in all, whereas MMP-9 activity, extracellular matrix metalloproteinase inducer (EMMPRIN), and expression of the two genes were analyzed in a subset of 240 randomly selected patients. Results Totally, 106 clinical endpoints were recorded. In MetS; the T-allele associated with 5.5 fold increase in event rate (p<0.0001), increased with number of MetS components, a 117% increase in total MMP-9 levels (TT homozygous, p = 0.05), significantly higher total- and endogenous active MMP-9 and TIMP-1 levels (p<0.01 all), and EMMPRIN was inversely correlated with pro- and endogenous active MMP-9 (p<0.05, both). In non-MetS; the T-allele was not associated with new events, nor higher MMP-9 levels. EMMPRIN was significantly correlated with total MMP-9 and TIMP-1 (p<0.01, both) and the two genes were inter-correlated (p<0.001). Conclusion In CAD patients with MetS, the MMP-9 T-allele increased the risk of clinical events, probably mediated through elevated MMP-9 levels and altered MMP-9 regulation. PMID:25191702

The MMP-9 -1562 C/T polymorphism in the presence of metabolic syndrome increases the risk of clinical events in patients with coronary artery disease.

PubMed

Opstad, Trine B; Arnesen, Harald; Pettersen, Alf Å; Seljeflot, Ingebjørg

2014-01-01

Elevated levels of matrix metalloproteinase (MMP)-9 have been associated with the metabolic syndrome (MetS) and cardiovascular events. The MMP-9 -1562 C/T polymorphism has furthermore been shown as a risk factor for coronary artery disease (CAD). The non-favourable cardiometabolic state in MetS may increase the risk. We aimed to investigate the influence of MMP-9 -1562 C/T polymorphism in subjects with CAD and MetS. Patients (n = 1000) with verified CAD stratified in Mets +/- (n = 244/756), were analyzed for the MMP-9 -1562 C/T polymorphism and related to clinical events after 2 years follow-up. Serum levels of total MMP-9 and tissue inhibitor of matrix metalloproteinases (TIMP)-1 were analyzed in all, whereas MMP-9 activity, extracellular matrix metalloproteinase inducer (EMMPRIN), and expression of the two genes were analyzed in a subset of 240 randomly selected patients. Totally, 106 clinical endpoints were recorded. In MetS; the T-allele associated with 5.5 fold increase in event rate (p<0.0001), increased with number of MetS components, a 117% increase in total MMP-9 levels (TT homozygous, p = 0.05), significantly higher total- and endogenous active MMP-9 and TIMP-1 levels (p<0.01 all), and EMMPRIN was inversely correlated with pro- and endogenous active MMP-9 (p<0.05, both). In non-MetS; the T-allele was not associated with new events, nor higher MMP-9 levels. EMMPRIN was significantly correlated with total MMP-9 and TIMP-1 (p<0.01, both) and the two genes were inter-correlated (p<0.001). In CAD patients with MetS, the MMP-9 T-allele increased the risk of clinical events, probably mediated through elevated MMP-9 levels and altered MMP-9 regulation.

Analytical performance of 17 general chemistry analytes across countries and across manufacturers in the INPUtS project of EQA organizers in Italy, the Netherlands, Portugal, United Kingdom and Spain.

PubMed

Weykamp, Cas; Secchiero, Sandra; Plebani, Mario; Thelen, Marc; Cobbaert, Christa; Thomas, Annette; Jassam, Nuthar; Barth, Julian H; Perich, Carmen; Ricós, Carmen; Faria, Ana Paula

2017-02-01

Optimum patient care in relation to laboratory medicine is achieved when results of laboratory tests are equivalent, irrespective of the analytical platform used or the country where the laboratory is located. Standardization and harmonization minimize differences and the success of efforts to achieve this can be monitored with international category 1 external quality assessment (EQA) programs. An EQA project with commutable samples, targeted with reference measurement procedures (RMPs) was organized by EQA institutes in Italy, the Netherlands, Portugal, UK, and Spain. Results of 17 general chemistry analytes were evaluated across countries and across manufacturers according to performance specifications derived from biological variation (BV). For K, uric acid, glucose, cholesterol and high-density density (HDL) cholesterol, the minimum performance specification was met in all countries and by all manufacturers. For Na, Cl, and Ca, the minimum performance specifications were met by none of the countries and manufacturers. For enzymes, the situation was complicated, as standardization of results of enzymes toward RMPs was still not achieved in 20% of the laboratories and questionable in the remaining 80%. The overall performance of the measurement of 17 general chemistry analytes in European medical laboratories met the minimum performance specifications. In this general picture, there were no significant differences per country and no significant differences per manufacturer. There were major differences between the analytes. There were six analytes for which the minimum quality specifications were not met and manufacturers should improve their performance for these analytes. Standardization of results of enzymes requires ongoing efforts.

Metabolic syndrome is not associated with greater evidences of proliferative inflammatory atrophy and inflammation in patients with suspected prostate cancer.

PubMed

Russo, Giorgio I; Cimino, Sebastiano; Giranio, Giorgia; Regis, Federica; Favilla, Vincenzo; Privitera, Salvatore; Motta, Fabio; Caltabiano, Rosario; Stenzl, Arnulf; Todenhöfer, Tilman; Morgia, Giuseppe

2018-05-01

To evaluate the association between metabolic syndrome (MetS) and proliferative inflammatory atrophy (PIA) in patients with suspected prostate cancer (PCa). From June 2015 to July 2016, we conducted the FIERY (Flogosis Increased Events of pRostatic biopsY) study at the Urology section, Department of Surgery of the University of Catania (Local registration number: #131/2015). A total of 205 patients with elevated prostate-specific antigen (≥ 4 ng/ml) or clinical suspicion of PCa who underwent primary transperineal prostate biopsy were included in this cross-sectional study. The assessment of PIA, HGPIN, and PCa were performed by 2 experienced pathologists and samples were investigated for the presence of an inflammatory infiltrate, according to the Irani score. Primary and secondary Gleason grade of tumor in positive biopsies were evaluated according to the 2016 ISUP Modified Gleason System. In the entire cohort, median age was 68.0 (interquartile range: 62.0-74.5), median prostate-specific antigen was 6.5 (interquartile range: 5.51-9.57). The prevalence of MetS was 34.1%, the detection rate of PCa was 32.7%, the rate of PIA was 28.3%, the rate of HGPIN was 32.2%, whereas the rate of severe intraprostatic inflammation (Irani-score ≥4) was 28.8%. When comparing clinical and histological variables in patients without and with PIA, metabolic aberrations where not significantly different in both groups. We did not find statistical association in detection rate of PCa (29.3% vs. 34.0%; P = 0.07) and HGPIN (27.6% vs. 34.0%; P = 0.37) in patients with and without PIA, respectively. When considering metabolic aberrations, MetS was not associated with Irani-score ≥4 (28.6% vs. 28.4%; P = 0.96) and none of each component was statistically predictive of severe inflammation. At the multivariable logistic regression analysis, PIA, HGPIN, and MetS were not associated with greater risk of PCa. In this study, we did not show an association between MetS and PIA and PCa. Although the small sample size and the cross-sectional nature of the study, we do not suppose that MetS could be associated with greater evidence of PIA. Further studies should be conducted to evaluate the exact nature of this pathological lesion. Copyright © 2018 Elsevier Inc. All rights reserved.

Landing and Population Hazard Analysis for Stardust Entry in Operations and Entry Planning

NASA Technical Reports Server (NTRS)

Tooley, Jeffrey; Desai, Prasun N.; Lynos, Daniel T.; Hirst, Edward A.; Wahl, Tom E.; Wawrzyniak, Georffery G.

2006-01-01

Stardust is a comet sample return mission that successfully returned to Earth on January 15, 2006. Stardust's targeted landing area was the Utah Test and Training Range in the Northwest corner of Utah. Requirements for the risks associated with landing were levied on Stardust by the Utah Test and Training Range and NASA. This paper describes the analysis to verify that these requirements were met and and includes calculation of debris survivability, generation of landing site selection plots, and identification of keep-out zones, as well as appropriate selection of the landing site. Operationally the risk requirements were all met for both of the GOMO-GO polls, so entry was authorized.

U.S. Selected Practice Recommendations for Contraceptive Use, 2016.

PubMed

Curtis, Kathryn M; Jatlaoui, Tara C; Tepper, Naomi K; Zapata, Lauren B; Horton, Leah G; Jamieson, Denise J; Whiteman, Maura K

2016-07-29

The 2016 U.S. Selected Practice Recommendations for Contraceptive Use (U.S. SPR) addresses a select group of common, yet sometimes controversial or complex, issues regarding initiation and use of specific contraceptive methods. These recommendations for health care providers were updated by CDC after review of the scientific evidence and consultation with national experts who met in Atlanta, Georgia, during August 26-28, 2015. The information in this report updates the 2013 U.S. SPR (CDC. U.S. selected practice recommendations for contraceptive use, 2013. MMWR 2013;62[No. RR-5]). Major updates include 1) revised recommendations for starting regular contraception after the use of emergency contraceptive pills and 2) new recommendations for the use of medications to ease insertion of intrauterine devices. The recommendations in this report are intended to serve as a source of clinical guidance for health care providers and provide evidence-based guidance to reduce medical barriers to contraception access and use. Health care providers should always consider the individual clinical circumstances of each person seeking family planning services. This report is not intended to be a substitute for professional medical advice for individual patients. Persons should seek advice from their health care providers when considering family planning options.

Novel Hybrid Virtual Screening Protocol Based on Molecular Docking and Structure-Based Pharmacophore for Discovery of Methionyl-tRNA Synthetase Inhibitors as Antibacterial Agents

PubMed Central

Liu, Chi; He, Gu; Jiang, Qinglin; Han, Bo; Peng, Cheng

2013-01-01

Methione tRNA synthetase (MetRS) is an essential enzyme involved in protein biosynthesis in all living organisms and is a potential antibacterial target. In the current study, the structure-based pharmacophore (SBP)-guided method has been suggested to generate a comprehensive pharmacophore of MetRS based on fourteen crystal structures of MetRS-inhibitor complexes. In this investigation, a hybrid protocol of a virtual screening method, comprised of pharmacophore model-based virtual screening (PBVS), rigid and flexible docking-based virtual screenings (DBVS), is used for retrieving new MetRS inhibitors from commercially available chemical databases. This hybrid virtual screening approach was then applied to screen the Specs (202,408 compounds) database, a structurally diverse chemical database. Fifteen hit compounds were selected from the final hits and shifted to experimental studies. These results may provide important information for further research of novel MetRS inhibitors as antibacterial agents. PMID:23839093

Sex based levels of C-reactive protein and white blood cell count in subjects with metabolic syndrome: Isfahan Healthy Heart Program.

PubMed

Gharipour, Mojgan; Ramezani, Mohammad Arash; Sadeghi, Masuomeh; Khosravi, Alireza; Masjedi, Mohsen; Khosravi-Boroujeni, Hossein; Rafieian-Kopaei, Mahmoud; Sarrafzadegan, Nizal

2013-06-01

C-reactive protein (CRP) and white blood cell (WBC) are proinflammatory markers. They are major pathophysiological for the development of metabolic syndrome (MetS). This study aimed to address the independent associations between MetS and WBC counts and serum CRP levels and evaluation of their magnitude in relation to the MetS, based on the sex in the Iranian adults. In this cross-sectional study, subjects who met the MetS criteria, based on the Adult Treatment Panel III were selected from the Isfahan Healthy Heart Program database. A questionnaire containing the demographic data, weight, height, waist, and hip circumference of the respondents was completed for each person. Blood pressure was measured and the anthropometric measurements were done, and fasting blood samples were taken for 2 h postload plasma glucose (2 hpp). Serum [total, high-density lipoprotein (HDL), and low-density lipoprotein] levels of cholesterol, triglyceride, and CRP as well as WBC counts were determined. The univariate analyses were carried out to assess the relation between the CRP levels, WBC counts with the MetS in both sexes the. In men with the abdominal obesity, the higher levels of WBC count, high serum triglyceride and blood glucose levels, a low serum HDL level, and raised systolic and diastolic blood pressure were observed. However, the higher serum CRP levels were only observed in those with the low serum HDL-cholesterol levels. The mean values of the WBC counts were statistically different between the men with and without MetS, but the mean values of the CRP levels were similar between the two groups. In women, the mean values of WBC count and CRP levels were statistically different in the subjects with and without a MetS components (except for the low serum HDL levels and high diastolic blood pressure for the WBC measures and abdominal obesity for the CRP measures) and for those with and without MetS. The age and smoking adjusted changes in the CRP levels and WBC counts correlated with the number of Mets components in the women. The findings of this study suggest substantial implications for the prevention and management of the MetS and atherosclerotic diseases, as these involve the suppression of inflammatory conditions rather than the incitement of anti-inflammatory conditions.

Discovery and SAR study of c-Met kinase inhibitors bearing an 3-amino-benzo[d]isoxazole or 3-aminoindazole scaffold.

PubMed

Jiang, Xiaolong; Liu, Hongyan; Song, Zilan; Peng, Xia; Ji, Yinchun; Yao, Qizheng; Geng, Meiyu; Ai, Jing; Zhang, Ao

2015-02-01

A series of 3-amino-benzo[d]isoxazole-/3-aminoindazole-based compounds were designed, synthesized and pharmacologically evaluated as tyrosine kinase c-Met inhibitors. The SAR study was conducted leading to identification of nine compounds (8d, 8e, 12, 28a-d, 28h and 28i) with IC50s less than 10nM against c-Met. Compound 28a stood out as the most potent c-Met inhibitor displaying potent inhibitory effects both at enzymatic (IC50=1.8 nM) and cellular (IC50=0.18 μM on EBC-1 cells) levels. In addition, 28a had a relatively good selectivity compared to a panel of our in-house 14 RTKs. Copyright © 2014 Elsevier Ltd. All rights reserved.

New AdoMet Analogues as Tools for Enzymatic Transfer of Photo-Cross-Linkers and Capturing RNA-Protein Interactions.

PubMed

Muttach, Fabian; Mäsing, Florian; Studer, Armido; Rentmeister, Andrea

2017-05-02

Elucidation of biomolecular interactions is of utmost importance in biochemistry. Photo-cross-linking offers the possibility to precisely determine RNA-protein interactions. However, despite the inherent specificity of enzymes, approaches for site-specific introduction of photo-cross-linking moieties into nucleic acids are scarce. Methyltransferases in combination with synthetic analogues of their natural cosubstrate S-adenosyl-l-methionine (AdoMet) allow for the post-synthetic site-specific modification of biomolecules. We report on three novel AdoMet analogues bearing the most widespread photo-cross-linking moieties (aryl azide, diazirine, and benzophenone). We show that these photo-cross-linkers can be enzymatically transferred to the methyltransferase target, that is, the mRNA cap, with high efficiency. Photo-cross-linking of the resulting modified mRNAs with the cap interacting protein eIF4E was successful with aryl azide and diazirine but not benzophenone, reflecting the affinity of the modified 5' caps. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Decreasing Prevalence of the Full Metabolic Syndrome but a Persistently High Prevalence of Dyslipidemia among Adult Arabs

PubMed Central

Al-Daghri, Nasser M.; Al-Attas, Omar S.; Alokail, Majed S.; Alkharfy, Khalid M.; Sabico, Shaun Louie B.; Chrousos, George P.

2010-01-01

A decade has passed since metabolic syndrome (MetS) was documented to be highly prevalent in the kingdom of Saudi Arabia. No follow-up epidemiologic study was done. This study aims to fill this gap. In this cross-sectional, observational study, a total of 2850 randomly selected Saudi adults aged 18–55 years were recruited. Subjects' information was generated from a database of more than 10,000 Saudi citizens from the existing Biomarkers Screening in Riyadh Program (RIYADH Cohort), Saudi Arabia. Anthropometrics included body mass index (BMI), blood pressure, as well as waist and hip circumferences. Fasting blood glucose and lipid profile were determined using routine laboratory procedures. The definition of ATP-III (NHANES III) was used for the diagnosis of the full MetS. The overall prevalence of complete MetS was 35.3% [Confidence-Interval (CI) 33.5–37.01]. Age-adjusted prevalence according to the European standard population is 37.0%. Low HDL-cholesterol was the most prevalent of all MetS risk factors, affecting 88.6% (CI 87.5–89.7) and hypertriglyceridemia the second most prevalent, affecting 34% (CI 32.3–35.7) of the subjects. The prevalence of the full MetS decreased from previous estimates but remains high, while dyslipidemia remains extremely high, affecting almost 90% of middle-aged Arabs. Screening for dyslipidemia among Saudi adults is warranted, especially among those most at risk. Scientific inquiry into the molecular causes of these manifestations should be pursued as a first step in the discovery of etiologic therapies. PMID:20730053

Decreasing prevalence of the full metabolic syndrome but a persistently high prevalence of dyslipidemia among adult Arabs.

PubMed

Al-Daghri, Nasser M; Al-Attas, Omar S; Alokail, Majed S; Alkharfy, Khalid M; Sabico, Shaun Louie B; Chrousos, George P

2010-08-13

A decade has passed since metabolic syndrome (MetS) was documented to be highly prevalent in the kingdom of Saudi Arabia. No follow-up epidemiologic study was done. This study aims to fill this gap. In this cross-sectional, observational study, a total of 2850 randomly selected Saudi adults aged 18-55 years were recruited. Subjects' information was generated from a database of more than 10,000 Saudi citizens from the existing Biomarkers Screening in Riyadh Program (RIYADH Cohort), Saudi Arabia. Anthropometrics included body mass index (BMI), blood pressure, as well as waist and hip circumferences. Fasting blood glucose and lipid profile were determined using routine laboratory procedures. The definition of ATP-III (NHANES III) was used for the diagnosis of the full MetS. The overall prevalence of complete MetS was 35.3% [Confidence-Interval (CI) 33.5-37.01]. Age-adjusted prevalence according to the European standard population is 37.0%. Low HDL-cholesterol was the most prevalent of all MetS risk factors, affecting 88.6% (CI 87.5-89.7) and hypertriglyceridemia the second most prevalent, affecting 34% (CI 32.3-35.7) of the subjects. The prevalence of the full MetS decreased from previous estimates but remains high, while dyslipidemia remains extremely high, affecting almost 90% of middle-aged Arabs. Screening for dyslipidemia among Saudi adults is warranted, especially among those most at risk. Scientific inquiry into the molecular causes of these manifestations should be pursued as a first step in the discovery of etiologic therapies.

Sociocultural Characteristic, Lifestyle, and Metabolic Risk Factors Among a Sample of Kuwaiti Male University Students

PubMed Central

Al-Sejari, Maha

2016-01-01

In the past six decades, the Kuwaiti population has been exposed to rapid transformation in the quality of diet intake, daily activities, and career types. This major socioeconomic shift was accompanied by the introduction of both communicable and noncommunicable chronic diseases afflicting people of all ages. This article aims to detect a relationship between sociocultural characteristics—such as physical activity, dietary habits, and smoking—and the prevalence of metabolic syndrome (MetS). A descriptive, cross-sectional survey was conducted among 262 male university students in Kuwait; participants were selected by using a convenient nonrandom opportunistic sample. Associated social and health factors were obtained using a closed-ended questionnaire. BMI and blood tests that include clusters of MetS risk components were drawn from participants in primary health care clinics. More than half of the participants were overweight and obese; 74.4% of the participants reported they did not visit a nutritionist; 69.8% said that they are currently not on a diet; 53.4% of the students were nonsmokers; 42.7% reported moderate to very low daily physical activity. The prevalence of MetS components increased among students with older age, employed, and married (p < .001), higher BMI, higher income, smoking, fewer number of family members living, and belonging to the Shia religious sect (p < .05). The high frequency of MetS among younger students needs to be considered by Kuwaiti community members and the government to highlight the risk factors of MetS on individuals’ well-being, quality of life, and life expectation. PMID:27903953

Familial aggregation and linkage analysis with covariates for metabolic syndrome risk factors.

PubMed

Naseri, Parisa; Khodakarim, Soheila; Guity, Kamran; Daneshpour, Maryam S

2018-06-15

Mechanisms of metabolic syndrome (MetS) causation are complex, genetic and environmental factors are important factors for the pathogenesis of MetS In this study, we aimed to evaluate familial and genetic influences on metabolic syndrome risk factor and also assess association between FTO (rs1558902 and rs7202116) and CETP(rs1864163) genes' single nucleotide polymorphisms (SNP) with low HDL_C in the Tehran Lipid and Glucose Study (TLGS). The design was a cross-sectional study of 1776 members of 227 randomly-ascertained families. Selected families contained at least one affected metabolic syndrome and at least two members of the family had suffered a loss of HDL_C according to ATP III criteria. In this study, after confirming the familial aggregation with intra-trait correlation coefficients (ICC) of Metabolic syndrome (MetS) and the quantitative lipid traits, the genetic linkage analysis of HDL_C was performed using conditional logistic method with adjusted sex and age. The results of the aggregation analysis revealed a higher correlation between siblings than between parent-offspring pairs representing the role of genetic factors in MetS. In addition, the conditional logistic model with covariates showed that the linkage results between HDL_C and three marker, rs1558902, rs7202116 and rs1864163 were significant. In summary, a high risk of MetS was found in siblings confirming the genetic influences of metabolic syndrome risk factor. Moreover, the power to detect linkage increases in the one parameter conditional logistic model regarding the use of age and sex as covariates. Copyright © 2018. Published by Elsevier B.V.

Sociocultural Characteristic, Lifestyle, and Metabolic Risk Factors Among a Sample of Kuwaiti Male University Students.

PubMed

Al-Sejari, Maha

2017-03-01

In the past six decades, the Kuwaiti population has been exposed to rapid transformation in the quality of diet intake, daily activities, and career types. This major socioeconomic shift was accompanied by the introduction of both communicable and noncommunicable chronic diseases afflicting people of all ages. This article aims to detect a relationship between sociocultural characteristics-such as physical activity, dietary habits, and smoking-and the prevalence of metabolic syndrome (MetS). A descriptive, cross-sectional survey was conducted among 262 male university students in Kuwait; participants were selected by using a convenient nonrandom opportunistic sample. Associated social and health factors were obtained using a closed-ended questionnaire. BMI and blood tests that include clusters of MetS risk components were drawn from participants in primary health care clinics. More than half of the participants were overweight and obese; 74.4% of the participants reported they did not visit a nutritionist; 69.8% said that they are currently not on a diet; 53.4% of the students were nonsmokers; 42.7% reported moderate to very low daily physical activity. The prevalence of MetS components increased among students with older age, employed, and married ( p < .001), higher BMI, higher income, smoking, fewer number of family members living, and belonging to the Shia religious sect ( p < .05). The high frequency of MetS among younger students needs to be considered by Kuwaiti community members and the government to highlight the risk factors of MetS on individuals' well-being, quality of life, and life expectation.

MAPK pathway inhibition induces MET and GAB1 levels, priming BRAF mutant melanoma for rescue by hepatocyte growth factor

PubMed Central

Caenepeel, Sean; Cooke, Keegan; Wadsworth, Sarah; Huang, Guo; Robert, Lidia; Moreno, Blanca Homet; Parisi, Giulia; Cajulis, Elaina; Kendall, Richard; Beltran, Pedro; Ribas, Antoni; Coxon, Angela; Hughes, Paul E.

2017-01-01

Therapeutic resistance is a major obstacle to achieving durable clinical responses with targeted therapies, highlighting a need to elucidate the underlying mechanisms responsible for resistance and identify strategies to overcome this challenge. An emerging body of data implicates the tyrosine kinase MET in mediating resistance to BRAF inhibitors in BRAFV600E mutant melanoma. In this study we observed a dominant role for the HGF/MET axis in mediating resistance to BRAF and MEK inhibitors in models of BRAFV600E and NRAS mutant melanoma. In addition, we showed that MAPK pathway inhibition induced rapid increases in MET and GAB1 levels, providing novel mechanistic insight into how BRAFV600E mutant melanoma is primed for HGF-mediated rescue. We also determined that tumor-derived HGF, not systemic HGF, may be required to convey resistance to BRAF inhibition in vivo and that resistance could be reversed following treatment with AMG 337, a selective MET inhibitor. In summary, these findings support the clinical evaluation of MET-directed targeted therapy to circumvent resistance to BRAF and MEK inhibitors in BRAFV600E mutant melanoma. In addition, the induction of MET following treatment with BRAF and MEK inhibitors has the potential to serve as a predictive biomarker for identifying patients best suited for MET inhibitor combination therapy. PMID:28147313

Association of anthropometric indices with continuous metabolic syndrome in children and adolescents: the CASPIAN-V study.

PubMed

Ejtahed, Hanieh-Sadat; Qorbani, Mostafa; Motlagh, Mohammad Esmaeil; Angoorani, Pooneh; Hasani-Ranjbar, Shirin; Ziaodini, Hasan; Taheri, Majzoubeh; Ahadi, Zeinab; Beshtar, Shaghayegh; Aminaee, Tahereh; Heshmat, Ramin; Kelishadi, Roya

2017-11-01

This study aims to examine the association of anthropometric indices with continuous metabolic syndrome (cMetS) among Iranian children and adolescents. This multicentric study was conducted on 14138 students aged 7-18 years, who participated in a national surveillance program. Fasting blood sample was obtained from a subsample of 3843 randomly selected students. Physical examination including the measurement of anthropometric indices and blood pressure was conducted; fasting blood glucose and lipid profile were measured; and cMetS score was computed. Standardized residuals (z-scores) were calculated for MetS components. A higher cMetS score indicates a less favorable metabolic profile. Linear regression models were applied to determine the association between cMetS and anthropometric indices. The study participants consisted of 3843 children and adolescents (52.3% boys) with mean (SD) age of 12.45 ± 3.04 years. All anthropometric indices had positive correlation with standardized scores of mean arterial pressure, waist circumference and cMetS (P < 0.05). Standardized scores of triglycerides were positively correlated with weight and body mass index (P < 0.05). In multivariate model, general and abdominal obesity, as well as high circumferences of neck, wrist, and hip circumferences increased the standardized cMetS risk score to 1.8, 1.9, 1.6, 1.5 and 1.5, respectively (P < 0.05 for all variables). The results demonstrated that higher anthropometric indices are associated with higher cMetS risk score in children and adolescents. This information could be valuable for screening and prevention of MetS at population level. V, cross-sectional descriptive study (National surveillance study).

Expression of ZmMET1, a gene encoding a DNA methyltransferase from maize, is associated not only with DNA replication in actively proliferating cells, but also with altered DNA methylation status in cold-stressed quiescent cells.

PubMed

Steward, N; Kusano, T; Sano, H

2000-09-01

A cDNA fragment encoding part of a DNA methyltransferase was isolated from maize. The putative amino acid sequence identically matched that deduced from a genomic sequence in the database (accession no. AF063403), and the corresponding gene was designated as ZmMET1. Bacterially expressed ZmMET1 actively methylated DNA in vitro. Transcripts of ZmMET1 could be shown to exclusively accumulate in actively proliferating cells of the meristems of mesocotyls and root apices, suggesting ZmMET1 expression to be associated with DNA replication. This was confirmed by simultaneous decrease of transcripts of ZmMET1 and histone H3, a marker for DNA replication, in seedlings exposed to wounding, desiccation and salinity, all of which suppress cell division. Cold stress also depressed both transcripts in root tissues. In contrast, however, accumulation of ZmMET1 transcripts in shoot mesocotyls was not affected by cold stress, whereas those for H3 sharply decreased. Such a differential accumulation of ZmMET1 transcripts was consistent with ZmMET1 protein levels as revealed by western blotting. Expression of ZmMET1 is thus coexistent, but not completely dependent on DNA replication. Southern hybridization analysis with a methylation-sensitive restriction enzyme revealed that cold treatment induced demethylation of DNA in the Ac/Ds transposon region, but not in other genes, and that such demethylation primarily occurred in roots. These results suggested that the methylation level was decreased selectively by cold treatment, and that ZmMET1 may, at least partly, prevent such demethylation.

Meta-analysis of the brain-derived neurotrophic factor gene (BDNF) Val66Met polymorphism in anxiety disorders and anxiety-related personality traits.

PubMed

Frustaci, Alessandra; Pozzi, Gino; Gianfagna, Francesco; Manzoli, Lamberto; Boccia, Stefania

2008-01-01

Brain-derived neurotrophic factor (BDNF) is potentially involved in the pathogenesis of anxiety. We carried out meta-analyses to evaluate the relationship between the BDNF Val66Met (valine, methionine) polymorphism and anxiety disorders (AD) or anxiety-related personality traits (ARPT). Medline, Embase and PsycINFO were searched up to December 2007. We investigated 3 outcomes related to BDNF Val66Met polymorphisms: (1) clinically diagnosed cases of AD; (2) ARPT in subjects without psychiatric diagnoses, assessed either by the Neuroticism scale of NEO-Personality Inventory forms (NEO-PI, NEO-PI-R, NEO-FFI), or by (3) the Harm Avoidance (HA) scale of Tridimensional Personality Questionnaire (TPQ) or its extended version Temperament and Character Inventory (TCI). Seven case-control studies were selected for AD, including 1,092 cases and 8,394 controls, while 5 cross-sectional studies for Neuroticism (n = 1,633) and 4 for HA (n = 607). Both Met/Met and Val/Met individuals, as compared to Val/Val, showed a statistically significant lower Neuroticism score [SMD = -0.24 (95% CI: -0.44, -0.04), and -0.11 (95% CI: -0.22, -0.01), respectively]. No significant association was found between BDNF Val66Met polymorphism and AD [OR = 1.13 (95% CI: 0.85-1.52) for Met/Met versus Val/Val] or HA [SMD = 0.11 (95% CI: -0.19, 0.42) for Met/Met vs. Val/Val]. The low number of studies on this topic and their limited sample size, along with the inner limits in the definition of anxiety phenotypes, suggest caution in the interpretation of these results. Larger additional studies possibly investigating the interaction with other genes and environmental exposures are required to confirm these results. 2008 S. Karger AG, Basel.

Marked testosterone deficiency-related symptoms may be associated to higher metabolic risk in men with low testosterone levels.

PubMed

García-Cruz, Eduard; Leibar-Tamayo, Asier; Romero-Otero, Javier; Asiaín, Ignacio; Carrión, Albert; Castañeda, Roberto; Mateu, Laura; Luque, Pilar; Cardeñosa, Oscar; Alcaraz, Antonio

2014-09-01

Testosterone deficiency syndrome (TDS) is usually suspected on the basis of signs/symptoms. However, some men with low testosterone levels (low T) are asymptomatic or present mild, unnoticed symptoms. Would they have the same cardiovascular risk as symptomatic men? This study aims to assess the relationship between presence/severity of low T-related symptoms and the likelihood of metabolic syndrome (MetS). Data were taken from a multicenter, cross-sectional study conducted in Spain among men visiting men's healthcare offices aged ≥45 with low T (total T <8 nmol/L or <12 nmol/L and calculated free T <250 nmol/L). Only subjects whose MetS components and symptoms had been assessed were selected. Data available included anthropometrics, toxic habits, comorbidities, and total testosterone (TT) levels. MetS was defined using the harmonized definition. Erectile dysfunction was classified using the International Index of Erectile Function questionnaire. The Ageing Male Symptoms (AMS) scale assessed symptoms. Symptom severity was classified as "none/mild" and "moderate/severe." Bivariate and multivariate logistic regression analyses were performed to calculate the effect of moderate/severe symptoms on the odds ratio (OR) for MetS. Mean age (SD) was 61.2 (8.1) years. Erectile dysfunction (ED), AMS, and MetS prevalence were 97.4%, 94.9%, and 69.6%. Prevalence of MetS was higher in men with moderate/severe symptoms vs. men with no/mild ones (75.3% vs. 57.9%, P < 0.001). Age and prevalence of TT <8 nmol/L, moderate/severe ED, and obesity were significantly higher in men with moderate/severe symptoms. Multivariate analysis showed that besides obesity and moderate/severe ED, moderate/severe symptoms increased the likelihood of MetS. This effect disappeared in men with severe ED and in the nonobese. Three symptoms showed relationship with MetS after adjusting for all confounding factors. Severity of TDS symptoms may indicate higher cardiovascular risk in men with low T. © 2014 International Society for Sexual Medicine.

Prevalence of metabolic syndrome in Iran: A meta-analysis

PubMed Central

Ostovar, Rahim; Kiani, Faezeh; Sayehmiri, Fatemeh; Yasemi, Masood; Mohsenzadeh, Yazdan; Mohsenzadeh, Yousof

2017-01-01

Background Metabolic syndrome) MetS( is a complex risk factor which increases the risk of cardiovascular diseases and type 2 diabetes. There are many studies with various populations and results about the prevalence of MetS in Iran; in order to authenticate these studies and have an overall estimation of its prevalence in Iran, performing a meta-analysis seems to be necessary. Objective This study aimed to investigate the prevalence of MetS and its components in Iran via meta-analysis method. Methods All associated published papers in national and international journals of PubMed, Scopus, Web of Science, Magiran, Iranmedex, Science Direct, Medlib, and SID databases were searched from January, 2000 to October, 2016. All types of studies, including local and national surveys that reported the prevalence of MetS among healthy populations in Iran were reviewed. The effects of age, sample size and publication date as possible sources of heterogeneity among the study findings was examined by meta-regression. P-values less than 0.05 were considered as significant in heterogeneity tests. All analysis was done by R Ver. 3.2.1 and STATA (version 10). Results Seventy eligible studies were selected for meta-analysis. The overall estimation of MetS prevalence was 25% (95% CI: 22–29%) based on the Adult Treatment Panel III (ATP III) criteria, 30% (95% CI: 25–36%) according to the International Diabetes Federation (IDF), and 39% (95% CI: 26–52%) based on the Joint Interim Societies (JIS) criteria. The prevalence of MetS was lower in men than in women (26.9% versus 35.7%). The prevalence of various MetS components including High TG (triglyceride), Low HDL-C, High BP and High FBS (fasting blood sugar) was 43%, 54%, 38% and 22% among the adult population. Conclusion Findings from the present meta-analyses study displayed a high prevalence of metabolic syndrome in Iran, especially in women, which increases with age in both sexes. It alerts health care providers and policy makers to find solutions in order to take action to reduce MetS risk in society. PMID:29238477

Substance P-induced respiratory excitation is blunted by delta-receptor specific opioids in the rat medulla oblongata.

PubMed

Chen, Z; Hedner, J; Hedner, T

1996-06-01

The effects of substance P (SP) and the naturally occurring met-enkephalin and the synthetic mu-specific opioid agonist, DAGO (Tyr-D-Ala-Gly-N-Methy-Phe-Gly-ol) and the delta-specific opioid agonist DADL (Tyr-D-Ala-Gly-Phe-D-Leu) on basal ventilation were investigated in halothane-anaesthetized rats. Local injections of SP (0.75-1.5 nmol) in the ventrolateral medulla oblongata (VLM), e.g. nucleus paragigantocellularis, and nucleus reticularis lateralis increased ventilation because of an elevation of tidal volume. Met-enkephalin induced a short-lasting ventilatory depression mainly because of a depression of tidal volume. Activation of delta- and mu-opioid receptors in the VLM by local application of DADL and DAGO, respectively, induced ventilatory depression, which was later in onset and more long-lasting. Local administration of met-enkephalin into the VLM also produced a long-lasting inhibition of the SP-induced ventilatory excitation. A similar blockade of the SP-induced excitatory ventilatory response could be elicited by DADL but not by DAGO. This antagonistic effect was attenuated by local application of the delta-opioid receptor antagonist ICI 154. 129. We conclude that the naturally occurring met-enkephalin as well as synthetic mu- and delta-specific enkephalin analogues (DAGO and DADL, respectively) in VLM depress basal ventilation by an effect on inspiratory drive. There is a functional antagonism between activation of delta-opioid receptors and SP receptors into the VLM in respect to respiratory regulation.

Selective laser melting of Inconel super alloy-a review

NASA Astrophysics Data System (ADS)

Karia, M. C.; Popat, M. A.; Sangani, K. B.

2017-07-01

Additive manufacturing is a relatively young technology that uses the principle of layer by layer addition of material in solid, liquid or powder form to develop a component or product. The quality of additive manufactured part is one of the challenges to be addressed. Researchers are continuously working at various levels of additive manufacturing technologies. One of the significant powder bed processes for met als is Selective Laser Melting (SLM). Laser based processes are finding more attention of researchers and industrial world. The potential of this technique is yet to be fully explored. Due to very high strength and creep resistance Inconel is extensively used nickel based super alloy for manufacturing components for aerospace, automobile and nuclear industries. Due to law content of Aluminum and Titanium, it exhibits good fabricability too. Therefore the alloy is ideally suitable for selective laser melting to manufacture intricate components with high strength requirements. The selection of suitable process for manufacturing for a specific component depends on geometrical complexity, production quantity, and cost and required strength. There are numerous researchers working on various aspects like metallurgical and micro structural investigations and mechanical properties, geometrical accuracy, effects of process parameters and its optimization and mathematical modeling etc. The present paper represents a comprehensive overview of selective laser melting process for Inconel group of alloys.

Chronic arsenic trioxide exposure leads to enhanced aggressiveness via Met oncogene addiction in cancer cells

PubMed Central

Kryeziu, Kushtrim; Pirker, Christine; Englinger, Bernhard; van Schoonhoven, Sushilla; Spitzwieser, Melanie; Mohr, Thomas; Körner, Wilfried; Weinmüllner, Regina; Tav, Koray; Grillari, Johannes; Cichna-Markl, Margit; Berger, Walter; Heffeter, Petra

2016-01-01

As an environmental poison, arsenic is responsible for many cancer deaths. Paradoxically, arsenic trioxide (ATO) presents also a powerful therapy used to treat refractory acute promyelocytic leukemia (APL) and is intensively investigated for treatment of other cancer types. Noteworthy, cancer therapy is frequently hampered by drug resistance, which is also often associated with enhancement of tumor aggressiveness. In this study, we analyzed ATO-selected cancer cells (A2780ATO) for the mechanisms underlying their enhanced tumorigenicity and aggressiveness. These cells were characterized by enhanced proliferation and spheroid growth as well as increased tumorigenicity of xenografts in SCID mice. Noteworthy, subsequent studies revealed that overexpression of Met receptor was the underlying oncogenic driver of these effects, as A2780ATO cells were characterized by collateral sensitivity against Met inhibitors. This finding was also confirmed by array comparative genomic hybridization (array CGH) and whole genome gene expression arrays, which revealed that Met overexpression by chronic ATO exposure was based on the transcriptional regulation via activation of AP-1. Finally, it was shown that treatment with the Met inhibitor crizotinib was also effective against A2780ATO cell xenografts in vivo, indicating that targeting of Met presents a promising strategy for the treatment of Met-overexpressing tumors after either arsenic exposure or failure to ATO treatment. PMID:27036042

Cardiorespiratory Fitness and Incidence of Major Adverse Cardiovascular Events in US Veterans: A Cohort Study.

PubMed

Kokkinos, Peter F; Faselis, Charles; Myers, Jonathan; Narayan, Puneet; Sui, Xuemei; Zhang, Jiajia; Lavie, Carl J; Moore, Hans; Karasik, Pamela; Fletcher, Ross

2017-01-01

To assess the association between exercise capacity and the risk of major adverse cardiovascular events (MACEs). A symptom-limited exercise tolerance test was performed to assess exercise capacity in 20,590 US veterans (12,975 blacks and 7615 whites; mean ± SD age, 58.2±11.0 years) from the Veterans Affairs medical centers in Washington, District of Columbia, and Palo Alto, California. None had a history of MACE or evidence of ischemia at the time of or before their exercise tolerance test. We established quintiles of cardiorespiratory fitness (CRF) categories based on age-specific peak metabolic equivalents (METs) achieved. We also defined the age-specific MET level associated with no risk for MACE (hazard ratio [HR], 1.0) and formed 4 additional CRF categories based on METs achieved below (least fit and low fit) and above (moderately fit and highly fit) that level. Multivariate Cox models were used to estimate HR and 95% CIs for mortality across fitness categories. During follow-up (median, 11.3 years; range, 0.3-33.0 years), 2846 individuals experienced MACEs. The CRF-MACE association was inverse and graded. The risk for MACE declined precipitously for those with a CRF level of 6.0 METs or higher. When considering CFR categories based on the age-specific MET threshold, the risk increased for those in the 2 CFR categories below that threshold (HR, 1.95; 95% CI, 1.73-2.21 and HR, 1.41; 95% CI, 1.27-1.56 for the least-fit and low-fit individuals, respectively) and decreased for those above it (HR, 0.77; 95% CI, 0.68-0.87 and HR, 0.57; 95% CI, 0.48-0.67 for moderately fit and highly fit, respectively). Increased CRF is inversely and independently associated with the risk for MACE. When an age-specific MET threshold was defined, the risk for MACE increased significantly for those below that threshold and decreased for those above it (P<.001). Published by Elsevier Inc.

Cannabinoids: Medical implications.

PubMed

Schrot, Richard J; Hubbard, John R

2016-01-01

Herbal cannabis has been used for thousands of years for medical purposes. With elucidation of the chemical structures of tetrahydrocannabinol (THC) and cannabidiol (CBD) and with discovery of the human endocannabinoid system, the medical usefulness of cannabinoids has been more intensively explored. While more randomized clinical trials are needed for some medical conditions, other medical disorders, like chronic cancer and neuropathic pain and certain symptoms of multiple sclerosis, have substantial evidence supporting cannabinoid efficacy. While herbal cannabis has not met rigorous FDA standards for medical approval, specific well-characterized cannabinoids have met those standards. Where medical cannabis is legal, patients typically see a physician who "certifies" that a benefit may result. Physicians must consider important patient selection criteria such as failure of standard medical treatment for a debilitating medical disorder. Medical cannabis patients must be informed about potential adverse effects, such as acute impairment of memory, coordination and judgment, and possible chronic effects, such as cannabis use disorder, cognitive impairment, and chronic bronchitis. In addition, social dysfunction may result at work/school, and there is increased possibility of motor vehicle accidents. Novel ways to manipulate the endocannbinoid system are being explored to maximize benefits of cannabinoid therapy and lessen possible harmful effects.

Children in school cafeterias select foods containing more saturated fat and energy than the Institute of Medicine recommendations.

USDA-ARS?s Scientific Manuscript database

In this study, we examined if children’s food selection met the School Meals Initiative (SMI) standards, and the recently released Institute of Medicine (IOM) recommendations. Mean food selection, plate waste, and food intake were also examined. Food intake of 2,049 4th-6th grade students were measu...

Children in school cafeterias select foods containing more saturated fat and energy than the institute of medicine recommends.

USDA-ARS?s Scientific Manuscript database

In this study, we examined if children’s food selections met the School Meals Initiative (SMI) standards, and the recently released Institute of Medicine (IOM) recommendations. Mean food selection, plate waste, and food intake were also examined. Food intake of 2,049 4th-6th grade students were meas...

Functional characterization of tachykinin NK1 receptors in the mouse uterus.

PubMed

Patak, Eva; Pennefather, Jocelyn N; Fleming, Anna; Story, Margot E

2002-12-01

1. Contractility studies were undertaken to determine the nature of the receptors mediating responses to tachykinins in uteri of oestrogen-treated mice. 2. In the presence of thiorphan (3 microM), captopril (10 microM), and bestatin (10 microM), substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) produced concentration-related contractions of uterine preparations. The order of potency was SP > or =NKA>NKB. 3. Neither atropine (0.1 microM) nor l-NOLA (100 microM), nor indomethacin (10 microM) alone or in combination with either ranitidine (10 microM) or mepyramine (10 microM), affected responses to SP. These findings indicate that SP actions are not mediated or modulated through the release of acetylcholine, nitric oxide, prostanoids or histamine. 4. In the presence of peptidase inhibitors, the tachykinin NK(1) receptor-selective agonist [Sar(9)Met(O(2))(11)]SP, produced a concentration-dependent contractile effect. The tachykinin NK(2) and NK(3) receptor-selective agonists [Lys(5)MeLeu(9)Nle(10)]NKA(4-10) and [MePhe(7)]NKB were relatively inactive. The potencies of SP analogues in which Glu replaced Gln(5) and/or Gln(6) were similar to that of SP. 5. The tachykinin NK(1) receptor-selective antagonist, SR140333 (10 nM), alone or combined with the tachykinin NK(2) receptor-selective antagonist, SR48968 (10 nM), shifted log concentration curves to SP, NKA and NKB to the right. SR140333 (10 nM) reduced the effect of [Sar(9)Met(O(2))(11)]SP. SR48968 did not affect responses to SP or [Sar(9)Met(O(2))(11)]SP, but reduced the effect of higher concentrations of NKA and shifted the log concentration-response curve to NKB to the right. The tachykinin NK(3) receptor-selective antagonist, SR 142801 (0.3 microM), had little effect on responses to SP and NKB. 6. We conclude that the tachykinin NK(1) receptor mediates contractile effects of SP, NKA and NKB and [Sar(9)Met(O(2))(11)]SP in myometrium from the oestrogen-primed mouse. The tachykinin NK(2) receptor may also participate in the responses to NKA and NKB.

MET Signaling Mediates Intestinal Crypt-Villus Development, Regeneration, and Adenoma Formation and Is Promoted by Stem Cell CD44 Isoforms.

PubMed

Joosten, Sander P J; Zeilstra, Jurrit; van Andel, Harmen; Mijnals, R Clinton; Zaunbrecher, Joost; Duivenvoorden, Annet A M; van de Wetering, Marc; Clevers, Hans; Spaargaren, Marcel; Pals, Steven T

2017-10-01

Resistance of metastatic human colorectal cancer cells to drugs that block epidermal growth factor (EGF) receptor signaling could be caused by aberrant activity of other receptor tyrosine kinases, activating overlapping signaling pathways. One of these receptor tyrosine kinases could be MET, the receptor for hepatocyte growth factor (HGF). We investigated how MET signaling, and its interaction with CD44 (a putative MET coreceptor regulated by Wnt signaling and highly expressed by intestinal stem cells [ISCs] and adenomas) affects intestinal homeostasis, regeneration, and adenoma formation in mini-gut organoids and mice. We established organoid cultures from ISCs stimulated with HGF or EGF and assessed intestinal differentiation by immunohistochemistry. Mice with total epithelial disruption of MET (Ah Cre /Met fl/fl /LacZ) or ISC-specific disruption of MET (Lgr5 Creert2 /Met fl/fl /LacZ) and control mice (Ah Cre /Met +/+ /LacZ, Lgr5 Creert2 /Met +/+ /LacZ) were exposed to 10 Gy total body irradiation; intestinal tissues were collected, and homeostasis and regeneration were assessed by immunohistochemistry. We investigated adenoma organoid expansion stimulated by HGF or EGF using adenomas derived from Lgr5 Creert2 /Met fl/fl /Apc fl/fl and Lgr5 Creert2 /Met +/+ /Apc fl/fl mice. The same mice were evaluated for adenoma prevalence and size. We also quantified adenomas in Ah Cre /Met fl/fl /Apc fl/+ mice compared with Ah Cre /Met +/+ /Apc fl/+ control mice. We studied expansion of organoids generated from crypts and adenomas, stimulated by HGF or EGF, that were derived from mice expressing different CD44 splice variants (Cd44 +/+ , Cd44 -/- , Cd44 s/s , or Cd44 v4-10/v4-10 mice). Crypts incubated with EGF or HGF expanded into self-organizing mini-guts with similar levels of efficacy and contained all differentiated cell lineages. MET-deficient mice did not have defects in intestinal homeostasis. Total body irradiation reduced numbers of proliferating crypts in Ah Cre /Met fl/fl /LacZ mice. Lgr5 Creert2 /Met fl/fl /LacZ mice had impaired regeneration of MET-deficient ISCs. Adenoma organoids stimulated with EGF or HGF expanded to almost twice the size of nonstimulated organoids. MET-deficient adenoma organoids did not respond to HGF stimulation, but did respond to EGF. ISC-specific disruption of Met (Lgr5 Creert2 /Met fl/fl /Apc fl/fl mice) caused a twofold increase in apoptosis in microadenomas, resulting in an approximately 50% reduction of microadenoma numbers and significantly reduced average adenoma size. Total epithelial disruption of Met (Ah Cre /Met fl/fl /Apc fl/+ mice) resulted in an approximate 50% reduction in (micro)adenoma numbers. Intestinal crypts from Cd44 -/- mice did not expand to the same extent as crypts from Cd44 +/+ mice on stimulation with HGF, but had the same response to EGF. The negative effect on HGF-mediated growth was overcome by expression of CD44v4-10, but not by CD44s. Similarly, HGF-mediated expansion of adenoma organoids required CD44v4-10. In studies of intestinal organoid cultures and mice with inducible deletion of MET, we found HGF receptor signaling to regulate intestinal homeostasis and regeneration, as well as adenoma formation. These activities of MET are promoted by the stem cell CD44 isoform CD44v4-10. Our findings provide rationale for targeting signaling via MET and CD44 during anti-EGF receptor therapy of patients with colorectal cancer or in patients resistant to EGF receptor inhibitors. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

A Scoring System to Predict the Severity of Hirschsprung Disease at Diagnosis and its Correlation with Molecular Genetics.

PubMed

Núñez-Ramos, Raquel; Fernández, Raquel M; González-Velasco, Miguel; Ruiz-Contreras, Jesús; Galán-Gómez, Enrique; Núñez-Núñez, Ramón; Borrego, Salud

2016-01-27

Hirschsprung disease (HSCR) has a wide range of severity. There are non-severe forms treated conservatively until surgery and severe forms that require an early stoma and prolonged hospitalization. Our objective was to establish a clinical scoring system to predict the severity of HSCR and to evaluate the possible existence of a clinical-genetic correlation. We carried out a retrospective observational study including all HSCR cases treated in our hospital. The sample was divided into severe and non-severe disease according to the number of surgical procedures, hospitalization time and episodes of enterocolitis. The proposed score was applied at diagnosis, and the sensitivity, specificity and optimal cut-point were determined. We conducted a prospective molecular study of RET, EDNRB and EDN3 on all patients, as well as SOX10 in Waardenburg Syndrome type 4 forms. Among the 42 patients treated between 1983 and 2013, 15 met the severe disease criteria. This group had a higher mean score (13.15±2.36) than the non-severe group (8.15±2.13; p<0.001). A score {greater than or equal to}11 had a sensitivity of 87% and a specificity of 81% in detecting the severe cases. Causative mutations were identified in 12 patients, 8 of them in the severe group (p=0.015). Most of these mutations (75%) were located in the RET proto-oncogene. The proposed scoring system enables the early selection of patients with severe behaviour of HSCR. A value {greater than or equal to}11 showed good sensitivity and specificity for this purpose. Causative mutations were identified in more than 50% of patients who met the criteria for severe disease.

A Scoring System to Predict the Severity of Hirschsprung Disease at Diagnosis and Its Correlation With Molecular Genetics.

PubMed

Núñez-Ramos, Raquel; Fernández, Raquel M; González-Velasco, Miguel; Ruiz-Contreras, Jesús; Galán-Gómez, Enrique; Núñez-Núñez, Ramón; Borrego, Salud

2017-01-01

Objectives Hirschsprung disease (HSCR) has a wide range of severity. There are nonsevere forms treated conservatively until surgery and severe forms that require an early stoma and prolonged hospitalization. Our objective was to establish a clinical scoring system to predict the severity of HSCR and to evaluate the possible existence of a clinical-genetic correlation. Methods We carried out a retrospective observational study including all HSCR cases treated in our hospital. The sample was divided into severe and nonsevere disease according to the number of surgical procedures, hospitalization time, and episodes of enterocolitis. The proposed score was applied at diagnosis, and the sensitivity, specificity, and optimal cut-point were determined. We conducted a prospective molecular study of RET, EDNRB, and EDN3 on all patients, as well as SOX10 in Waardenburg Syndrome type 4 forms. Results Among the 42 patients treated between 1983 and 2013, 15 met the severe disease criteria. This group had a higher mean score (13.15 ± 2.36) than the nonsevere group (8.15 ± 2.13; p < 0.001). A score ≥11 had a sensitivity of 87% and a specificity of 81% in detecting the severe cases. Causative mutations were identified in 12 patients, 8 of them in the severe group ( p = 0.015). Most of these mutations (75%) were located in the RET proto-oncogene. Conclusion The proposed scoring system enables the early selection of patients with severe behavior of HSCR. A value ≥11 showed good sensitivity and specificity for this purpose. Causative mutations were identified in more than 50% of patients who met the criteria for severe disease.

Greater impairment of postprandial triacylglycerol than glucose response in metabolic syndrome subjects with fasting hyperglycaemia.

PubMed

Jackson, Kim G; Walden, Charlotte M; Murray, Peter; Smith, Adrian M; Minihane, Anne M; Lovegrove, Julie A; Williams, Christine M

2013-08-01

Studies have started to question whether a specific component or combinations of metabolic syndrome (MetS) components may be more important in relation to cardiovascular disease risk. Our aim was to examine the impact of the presence of raised fasting glucose as a MetS component on postprandial lipaemia. Men classified with the MetS underwent a sequential test meal investigation, in which blood samples were taken at regular intervals after a test breakfast (t=0 min) and lunch (t=330 min). Lipids, glucose and insulin were measured in the fasting and postprandial samples. MetS subjects with 3 or 4 components were subdivided into those without (n=34) and with (n=23) fasting hyperglycaemia (≥5.6 mmol/l), irrespective of the combination of components. Fasting lipids and insulin were similar in the two groups, with glucose significantly higher in the men with glucose as a MetS component (P<0.001). Following the test meals, there were higher maximum concentration (maxC), area under the curve (AUC) and incremental AUC (P ≤0.016) for the postprandial triacylglycerol (TAG) response in men with fasting hyperglycaemia. Greater glucose AUC (P<0.001) and insulin maxC (P=0.010) were also observed in these individuals after the test meals. Multiple regression analysis revealed fasting glucose to be an important predictor of the postprandial TAG and glucose response. Our data analysis has revealed a greater impairment of postprandial TAG than glucose response in MetS subjects with raised fasting glucose. The worsening of postprandial lipaemic control may contribute to the greater CVD risk reported in individuals with MetS component combinations which include hyperglycaemia. Copyright © 2013 Elsevier Inc. All rights reserved.

Waist circumference is a potential indicator of metabolic syndrome in Singaporean Chinese.

PubMed

Nurjono, Milawaty; Lee, Jimmy

2013-05-01

Metabolic Syndrome (MetS) is associated with cardiovascular morbidity and mortality. Studies proposed that waist circumference (WC) and body mass index (BMI) are good indicators of MetS. In this study, we examined and compared the predictive utility of clinical measures such as WC, blood pressure and BMI and determined the cutoff points in which these measures are most reliable in identifying MetS in Singaporean Chinese. Two hundred and forty-four subjects aged between 21 and 50 years of Chinese ethnicity were recruited into the study. Sociodemographic, height, weight and blood pressure information were obtained. High-density lipoprotein cholesterol (HDL-C), triglycerides (TG) and glucose levels were evaluated. Presence of MetS was examined according to American Heart Association (AHA)/National Heart, Lung and Blood Institute (NHLBI) guidelines. Predictive utility of BP, WC and BMI was examined using receiver operating curve and discriminant indices were determined accordingly. Forty-one (16.8%) subjects were identified to have MetS. Our analysis revealed that waist circumference was most accurate in identifying MetS (area under the curve (AUC) = 0.88, 95% confidence interval (CI), 0.83 to 0.93, P <0.001) followed by BMI (AUC = 0.84, 95% CI, 0.77 to 0.91, P = 0.035), systolic BP (AUC = 0.83, 95% CI, 0.76 to 0.90, P = 0.036) and diastolic BP (AUC = 0.80, 95% CI, 0.71 to 0.88, P = 0.042). Waist circumference cut-off values of >92.5 cm in males and >86.5 cm in females were found to be most sensitive and specific in discriminating MetS. Our finding has immediate and significant clinical implications as WC can be easily obtained. However, as the study included only Singaporean Chinese, findings cannot be generalised for other ethnic groups.

Prevalence of Metabolic Syndrome among Malaysians using the International Diabetes Federation, National Cholesterol Education Program and Modified World Health Organization Definitions.

PubMed

Bee, Ying Tan; Haresh, Kumar Kantilal; Rajibans, Singh

2008-03-01

The World Health Organization (WHO), National Cholesterol Education Program Adults Treatment Panel III (NCEP ATP III) and International Diabetes Federation (IDF) have proposed different criteria to diagnose metabolic syndrome (MetS). However, there is no single definition to accurately diagnose MetS. The objective of this study is to estimate the prevalence of MetS using WHO, NCEP ATP III and IDF in the Malaysian community, and to determine the concordance between these definitions for MetS. 109 men and women aged > 30 years participated in the study, and the prevalence of MetS was determined according to the three definitions. Weight, height, body mass index (BMI), waist-hip circumference, blood pressure, blood lipid profile and plasma fasting glucose were measured. In order to determine the concordance between IDF and the other two definitions, the kappa index (κ-test) was used. The prevalence of MetS (95% confidence interval) was 22.9% (22.8-23.1) by IDF definition, 16.5% (16.3-16.9) by NCEP ATP III definition and 6.4% (6.2-6.6) by modified WHO definition. The sensitivity and specificity of IDF against NCEP ATP III were 88.9% and 90.1% respectively, IDF against WHO definition were 85.7% and 81.4%. The κ statistics for the agreement of the IDF definition was 68.3 ± 0.1 with the NCEP ATP III, and 30.5 ± 0.1 with the modified WHO definition. The prevalence of the MetS among respondents using the IDF definition was highest, followed by NCEP ATP III, and finally modified WHO definition. There was a good concordance between the IDF and NCEP ATP III definitions, and a low concordance between IDF and modified WHO definitions.

Differential Genetic and Epigenetic Regulation of catechol-O-methyltransferase is Associated with Impaired Fear Inhibition in Posttraumatic Stress Disorder.

PubMed

Norrholm, Seth Davin; Jovanovic, Tanja; Smith, Alicia K; Binder, Elisabeth; Klengel, Torsten; Conneely, Karen; Mercer, Kristina B; Davis, Jennifer S; Kerley, Kimberly; Winkler, Jennifer; Gillespie, Charles F; Bradley, Bekh; Ressler, Kerry J

2013-01-01

The catechol-O-methyltransferase (COMT) enzyme is critical for the catabolic regulation of synaptic dopamine, resulting in altered cortical functioning. The COMT Val(158)Met polymorphism has been implicated in human mental illness, with Met/Met homozygotes associated with increased susceptibility to posttraumatic stress disorder (PTSD). Our primary objective was to examine the intermediate phenotype of fear inhibition in PTSD stratified by COMT genotype (Met/Met, Val/Met, and Val/Val) and differential gene regulation via methylation status at CpG sites in the COMT promoter region. More specifically, we examined the potential interaction of COMT genotype and PTSD diagnosis on fear-potentiated startle during fear conditioning and extinction and COMT DNA methylation levels (as determined using genomic DNA isolated from whole blood). Participants were recruited from medical and gynecological clinics of an urban hospital in Atlanta, GA, USA. We found that individuals with the Met/Met genotype demonstrated higher fear-potentiated startle to the CS- (safety signal) and during extinction of the CS+ (danger signal) compared to Val/Met and Val/Val genotypes. The PTSD+ Met/Met genotype group had the greatest impairment in fear inhibition to the CS- (p = 0.006), compared to Val carriers. In addition, the Met/Met genotype was associated with DNA methylation at four CpG sites, two of which were associated with impaired fear inhibition to the safety signal. These results suggest that multiple differential mechanisms for regulating COMT function - at the level of protein structure via the Val(158)Met genotype and at the level of gene regulation via differential methylation - are associated with impaired fear inhibition in PTSD.

A comprehensive analysis of clinical outcomes in lung cancer patients harboring a MET exon 14 skipping mutation compared to other driver mutations in an East Asian population.

PubMed

Gow, Chien-Hung; Hsieh, Min-Shu; Wu, Shang-Gin; Shih, Jin-Yuan

2017-01-01

Recurrent somatic splice-site alterations at MET exon 14 (MET Δ14 ), which result in exon skipping and MET proto-oncogene, receptor tyrosine kinase (MET) activation, have been characterised. However, their demographic features and clinical outcomes in East Asian lung cancer patients have yet to be determined. A one-step reverse transcription-polymerase chain reaction (RT-PCR), using RNA samples from 850 East Asian lung cancer patients, was performed in order to detect MET Δ14 and five other major driver mutations, including those in the EGFR, KRAS, ALK, HER2, and ROS1 genes. Immunohistochemistry (IHC) was used to confirm the overexpression of MET in patients harbouring the MET Δ14 mutation. We analysed the demographic data and clinical outcomes of MET Δ14 mutation positive lung cancer patients and compared them to those of MET Δ14 mutation negative lung cancer patients. In total, 27 lung adenocarcinoma (ADC) patients and 1 squamous cell carcinoma patient with the MET Δ14 mutation were identified. The overall incidence was 3.3% for lung cancer and 4.0% for lung ADC. IHC demonstrated that the majority of lung cancer patients harboring a MET Δ14 mutation exhibited a strong cytoplasmic expression of MET. MET Δ14 mutation positive patients were generally quite elderly individuals. Stage IV MET Δ14 mutation positive lung cancer patients receiving no specific anti-MET therapy were observed to have a similar overall survival (OS) compared to patients in the all negative group (P>0.05). In the multivariate analysis, mutation status was found not to be a major risk factor for OS in lung cancer patients without appropriate tyrosine kinase inhibitors treatment. The OS of MET Δ14 mutation positive lung cancer patients is comparable to that of the major driver gene mutation negative lung cancer patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Effects of supplemental coated or crystalline methionine in low-fishmeal diet on the growth performance and body composition of juvenile cobia Rachycentron canadum (Linnaeus)

NASA Astrophysics Data System (ADS)

Chi, Shuyan; Tan, Beiping; Dong, Xiaohui; Yang, Qihui; Liu, Hongyu

2014-11-01

We evaluated the effects of supplemental coated and crystalline methionine (Met) on the growth performance and feed utilization of juvenile cobia ( Rachycentron canadum Linnaeus) in a 60-d feeding trial. Fish groups were fed one of six isonitrogenous and isolipidic diets: 1) fishmeal control; 2) un-supplemented experimental (low-fish-meal diet deficient in Met); or 3) one of four Met diets supplemented with crystalline L-Met, cellulose-acetate-phthalate coated L-Met, acrylic-resin coated L-Met, or tripalmitin-polyvinyl alcohol coated L-Met. The test diets were fed to triplicate groups of cobia (initial body weight 5.40±0.07 g) twice a day. The weight gain and specific growth rate of the fish fed the RES diet were highest among the Met-supplemented groups and were 23.64% and 7.99%, respectively, higher than those of the fish fed with the un-supplemented experimental diet ( P<0.05). The protein efficiency ratio of the fish fed the MET diet was significantly higher than that of the fish fed the un-supplemented experimental diet and the fish in the other methionine supplementation groups ( P<0.05). Our results suggest that supplementation of crystalline Met in low-fish-meal diets promotes the growth performance of juvenile cobia.

Inhibition of c-Met as a Therapeutic Strategy for Esophageal Adenocarcinoma

PubMed Central

Watson, Gregory A; Zhang, Xinglu; Stang, Michael T; Levy, Ryan M; Queiroz de Oliveira, Pierre E; Gooding, William E; Christensen, James G; Hughes, Steven J

2006-01-01

Abstract The hepatocyte growth factor (HGF) receptor c-Met is a tyrosine kinase receptor with established oncogenic properties. We have previously shown that c-Met is usually overexpressed in esophageal adenocarcinoma (EA), yet the implications of c-Met inhibition in EA remain unknown. Three c-Met-overexpressing EA cell lines (Seg-1, Bic-1, and Flo-1) were used to examine the effects of a c-Met-specific small molecule inhibitor (PHA665752) on cell viability, apoptosis, motility, invasion, and downstream signaling pathways. PHA665752 demonstrated dose-dependent inhibition of constitutive and/or HGF-induced phosphorylation of c-Met, which correlated with reduced cell viability and inhibition of extracellular regulated kinase 1/2 phosphorylation in all three EA cell lines. In contrast, PHA665752 induced apoptosis and reduced motility and invasion in only one EA cell line, Flo-1. Interestingly, Flo-1 was the only cell line in which phosphatidylinositol 3-kinase (PI3K)/Akt was induced following HGF stimulation. The PI3K inhibitor LY294002 produced effects equivalent to those of PHA665752 in these cells. We conclude that inhibition of c-Met may be a useful therapeutic strategy for EA. Factors other than receptor overexpression, such as c-Met-dependent PI3K/Akt signaling, may be predictive of an individual tumor's response to c-Met inhibition. PMID:17132227

Understanding Attrition in UK Maritime Education and Training

ERIC Educational Resources Information Center

Gekara, Victor

2009-01-01

The shipping industry worldwide is experiencing a shortage of trained and qualified officers to operate a rapidly expanding global merchant fleet. High cadet wastage in Maritime Education and Training (MET) institutions is an obstacle to skills replenishment in the UK. This paper examines the specificity of MET programmes with regard to the…

Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by Transmembrane O-methyltransferase (Tomt)

PubMed Central

Erickson, Timothy; Morgan, Clive P; Olt, Jennifer; Hardy, Katherine; Busch-Nentwich, Elisabeth; Maeda, Reo; Clemens, Rachel; Krey, Jocelyn F; Nechiporuk, Alex; Barr-Gillespie, Peter G; Marcotti, Walter; Nicolson, Teresa

2017-01-01

Transmembrane O-methyltransferase (TOMT/LRTOMT) is responsible for non-syndromic deafness DFNB63. However, the specific defects that lead to hearing loss have not been described. Using a zebrafish model of DFNB63, we show that the auditory and vestibular phenotypes are due to a lack of mechanotransduction (MET) in Tomt-deficient hair cells. GFP-tagged Tomt is enriched in the Golgi of hair cells, suggesting that Tomt might regulate the trafficking of other MET components to the hair bundle. We found that Tmc1/2 proteins are specifically excluded from the hair bundle in tomt mutants, whereas other MET complex proteins can still localize to the bundle. Furthermore, mouse TOMT and TMC1 can directly interact in HEK 293 cells, and this interaction is modulated by His183 in TOMT. Thus, we propose a model of MET complex assembly where Tomt and the Tmcs interact within the secretory pathway to traffic Tmc proteins to the hair bundle. DOI: http://dx.doi.org/10.7554/eLife.28474.001 PMID:28534737

Adiponectin/(FBG × FIns) as a predictor of insulin sensitivity and metabolic syndrome in patients with polycystic ovary syndrome.

PubMed

Xu, Xiaohui; Lai, Yerui; Yang, Gangyi; Yang, Mengliu; Li, Ling; Zhang, Qin; Liu, Hua; Zheng, Hongting; Zhu, Danping

2016-12-01

The euglycemic-hyperinsulinemic clamp is not available in most clinical settings. An accessible and inexpensive measurement for identifying insulin resistance (IR) is necessary. Our aim is to assess whether the adiponectin (ADI) index (ADI/[FBG × FIns]) is a better surrogate index for the assessment of IR or metabolic syndrome (MetS).A population-based cross-sectional study was conducted including 100 healthy women and 99 polycystic ovary syndrome patients. The euglycemic-hyperinsulinemic clamp was performed. Circulating ADI levels were determined by ELISA.Polycystic ovary syndrome and polycystic ovary syndrome plus MetS subjects had higher products of fasting triglycerides and glucose (TyG), Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), increased ratios of the area under the curve for insulin/the area under the curve for glucose (AUCi/AUCg), but lower ADI index as compared with healthy subjects. Partial correlation analysis in all populations showed that the M-value was significantly negatively correlated with HOMA-IR, TyG, TG/HDL, and AUCi/AUCg, and correlated positively with the ADI index. The r value of Pearson correlation between the ADI index and M-value was greater than that of the correlation between HOMA-IR, TyG, TG/HDL-C, and AUCi/AUCg. The optimal cut-off value of the ADI index for detection of IR was 0.67, with a sensitivity of 89.4% and a specificity of 88.1%, whereas for detection of MetS, it was 0.32, with a sensitivity of 88.7% and a specificity of 71.0%.The ADI index may be a surrogate marker in detecting IR and MetS.

Moderate Increase of Mean Daily Temperature Adversely Affects Fruit Set of Lycopersicon esculentum by Disrupting Specific Physiological Processes in Male Reproductive Development

PubMed Central

SATO, S.; KAMIYAMA, M.; IWATA, T.; MAKITA, N.; FURUKAWA, H.; IKEDA, H.

2006-01-01

• Background and Aims Global warming is gaining significance as a threat to natural and managed ecosystems since temperature is one of the major environmental factors affecting plant productivity. Hence, the effects of moderate temperature increase on the growth and development of the tomato plant (Lycopersicon esculentum) were investigated. • Methods Plants were grown at 32/26 °C as a moderately elevated temperature stress (METS) treatment or at 28/22 °C (day/night temperatures) as a control with natural light conditions. Vegetative growth and reproductive development as well as sugar content and metabolism, proline content and translocation in the androecium were investigated. • Key Results METS did not cause a significant change in biomass, the number of flowers, or the number of pollen grains produced, but there was a significant decrease in the number of fruit set, pollen viability and the number of pollen grains released. Glucose and fructose contents in the androecium (i.e. all stamens from one flower) were generally higher in the control than METS, but sucrose was higher in METS. Coincidently, the mRNA transcript abundance of acid invertase in the androecium was decreased by METS. Proline contents in the androecium were almost the same in the control and METS, while the mRNA transcript level of proline transporter 1, which expresses specifically at the surface of microspores, was significantly decreased by METS. • Conclusions The research indicated that failure of tomato fruit set under a moderately increased temperature above optimal is due to the disruption of sugar metabolism and proline translocation during the narrow window of male reproductive development. PMID:16497700

Comparison of Accuracy of Diabetes Risk Score and Components of the Metabolic Syndrome in Assessing Risk of Incident Type 2 Diabetes in Inter99 Cohort

PubMed Central

Shafizadeh, Tracy B.; Moler, Edward J.; Kolberg, Janice A.; Nguyen, Uyen Thao; Hansen, Torben; Jorgensen, Torben; Pedersen, Oluf; Borch-Johnsen, Knut

2011-01-01

Background Given the increasing worldwide incidence of diabetes, methods to assess diabetes risk which would identify those at highest risk are needed. We compared two risk-stratification approaches for incident type 2 diabetes mellitus (T2DM); factors of metabolic syndrome (MetS) and a previously developed diabetes risk score, PreDx® Diabetes Risk Score (DRS). DRS assesses 5 yr risk of incident T2DM based on the measurement of 7 biomarkers in fasting blood. Methodology/Principal Findings DRS was evaluated in baseline serum samples from 4,128 non-diabetic subjects in the Inter99 cohort (Danes aged 30–60) for whom diabetes outcomes at 5 years were known. Subjects were classified as having MetS based on the presence of at least 3 MetS risk factors in baseline clinical data. The sensitivity and false positive rate for predicting diabetes using MetS was compared to DRS. When the sensitivity was fixed to match MetS, DRS had a significantly lower false positive rate. Similarly, when the false positive rate was fixed to match MetS, DRS had a significantly higher specificity. In further analyses, subjects were classified by presence of 0–2, 3 or 4–5 risk factors with matching proportions of subjects distributed among three DRS groups. Comparison between the two risk stratification schemes, MetS risk factors and DRS, were evaluated using Net Reclassification Improvement (NRI). Comparing risk stratification by DRS to MetS factors in the total population, the NRI was 0.146 (p = 0.008) demonstrating DRS provides significantly improved stratification. Additionally, the relative risk of T2DM differed by 15 fold between the low and high DRS risk groups, but only 8-fold between the low and high risk MetS groups. Conclusions/Significance DRS provides a more accurate assessment of risk for diabetes than MetS. This improved performance may allow clinicians to focus preventive strategies on those most in need of urgent intervention. PMID:21829540

The utility of fat mass index vs. body mass index and percentage of body fat in the screening of metabolic syndrome.

PubMed

Liu, Pengju; Ma, Fang; Lou, Huiping; Liu, Yanping

2013-07-03

It has been well documented that obesity is closely associated with metabolic syndrome (MetS). Although body mass index (BMI) is the most frequently used method to assess overweightness and obesity, this method has been criticized because BMI does not always reflect true body fatness, which may be better evaluated by assessment of body fat and fat-free mass. The objective of this study was to investigate the best indicator to predict the presence of MetS among fat mass index, BMI and percentage of body fat (BF %) and determine its optimal cut-off value in the screening of MetS in practice. A cross-sectional study of 1698 subjects (aged 20-79 years) who participated in the annual health check-ups was employed. Body composition was measured by bioelectrical impedance analysis (BIA). Fat mass index (FMI) was calculated. Sex-specific FMI quartiles were defined as follows: Q1: <4.39, Q2:4.39- < 5.65, Q3:5.65- < 7.03, Q4:≥7.03,in men; and Q1:<5.25, Q2:5.25- < 6.33, Q3:6.33- < 7.93,Q4:≥7.93, in women. MetS was defined by National Cholesterol Education Program/Adult Treatment Panel III criteria. The association between FMI quartiles and MetS was assessed using Binary logistic regression. Receiver operating curve (ROC) analysis was used to determine optimal cutoff points for BMI,BF% and FMI in relation to the area under the curve (AUC), sensitivity and specificity in men and women. The adjusted odds ratios (95% CI) for the presence of MetS in the highest FMI quartile versus lowest quartile were 79.143(21.243-294.852) for men (P < 0.01) and 52.039(4.144-653.436) for women (P < 0.01) after adjusting age, BMI, BF%, TC, LDL, CRP, smoking status and exercise status, and the odds ratios were 9.166(2.157-38.952) for men (P < 0.01) and 25.574(1.945-336.228) for women (P < 0.05) when WC was also added into the adjustment. It was determined that BMI values of 27.45 and 23.85 kg/m2, BF% of 23.95% and 31.35% and FMI of 7.00 and 7.90 kg/m2 were the optimal cutoff values to predict the presence of MetS among men and women according to the ROC curve analysis. Among the indicators used to predict MetS, FMI was the index that showed the greatest area under the ROC curve in both sexes. Higher FMI levels appear to be independently and positively associated with the presence of MetS regardless of BMI and BF%. FMI seems to be a better screening tool in prediction of the presence of metabolic syndrome than BMI and percentage of body fat in men and women.

The performance of diphoton primary vertex reconstruction methods in H → γγ+Met channel of ATLAS experiment

NASA Astrophysics Data System (ADS)

Tomiwa, K. G.

2017-09-01

The search for new physics in the H → γγ+met relies on how well the missing transverse energy is reconstructed. The Met algorithm used by the ATLAS experiment in turns uses input variables like photon and jets which depend on the reconstruction of the primary vertex. This document presents the performance of di-photon vertex reconstruction algorithms (hardest vertex method and Neural Network method). Comparing the performance of these algorithms for the nominal Standard Model sample and the Beyond Standard Model sample, we see the overall performance of the Neural Network method of primary vertex selection performed better than the Hardest vertex method.

Profile of neuronal excitation following selective activation of the neurokinin-1 receptor in rat deep dorsal horn in vitro.

PubMed

King, A E; Ackley, M A; Slack, J R

1997-08-29

The excitatory actions of the selective neurokinin-1 receptor (NK1R) agonist [Sar9,Met(O2)11]substance P (SP) were tested on a sample (n = 50) of deep dorsal horn neurones in the isolated and hemisected young rat spinal cord. Superfusion of the NK1R agonist (2 microM) elicited a prolonged membrane depolarisation (6.6 +/- 0.5 mV) and an increase in action potential firing in 41/50 (82%) neurones. These [Sar9,Met(O2)11]SP-induced depolarisations were attenuated by the selective NK1R antagonist GR82334 (1 microM). An increased neuronal excitability after [Sar9,Met(O2)11]SP application was indicated by an augmented spike frequency generated in response to long duration, step depolarisations. In order to assess whether a direct excitatory action existed, [Sar9,Met(O2)11]SP was re-tested on a sample of TTX-treated neurones (n = 14). The majority (9/14) retained agonist sensitivity although the amplitude of the depolarisation was reduced to 48% of the control value. A sample of neurones (n = 7) that responded to the NK1R agonist were morphologically characterised after filling with the intracellular dye, biocytin. Dorsal dendrites that clearly penetrated lamina II and that could receive a direct C-afferent input, were identified in only 2/7 neurones. These electrophysiological and neuroanatomical data demonstrate that deep dorsal horn neurones possess functional NK1Rs. The implications of the existence of these NK1Rs in the context of spinal somatosensory systems and SP is considered.

21-Methylpyrenyl-cholesterol stably and specifically associates with lipoprotein peripheral hemi-membrane: A new labelling tool

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gaibelet, Gérald; CEA, SB2SM and UMR8221 CNRS, IBiTec-Saclay, Gif-sur-Yvette; Tercé, François

Highlights: •21-Methylpyrenyl-cholesterol specifically and stably associates to lipoproteins. •It is not esterified by LCAT, and thus reliably labels their peripheral hemi-membrane. •HDL vs. LDL are well distinguishable by various fluorescent labelling characteristics. •LDL peripheral hemi-membrane harbors cholesterol-rich ordered lipid (micro)domains. •Cultured cells can be stained by such labelled lipoproteins-mediated delivery. -- Abstract: Lipoproteins are important biological components. However, they have few convenient fluorescent labelling probes currently reported, and their physiological reliability can be questioned. We compared the association of two fluorescent cholesterol derivatives, 22-nitrobenzoxadiazole-cholesterol (NBD-Chol) and 21-methylpyrenyl-cholesterol (Pyr-met-Chol), to serum lipoproteins and to purified HDL and LDL. Both lipoproteins couldmore » be stably labelled by Pyr-met-Chol, but virtually not by NBD-Chol. At variance with NBD-Chol, LCAT did not esterify Pyr-met-Chol. The labelling characteristics of lipoproteins by Pyr-met-Chol were well distinguishable between HDL and LDL, regarding dializability, associated probe amount and labelling kinetics. We took benefit of the pyrene labelling to approach the structural organization of LDL peripheral hemi-membrane, since Pyr-met-Chol-labelled LDL, but not HDL, presented a fluorescence emission of pyrene excimers, indicating that the probe was present in an ordered lipid micro-environment. Since the peripheral membrane of LDL contains more sphingomyelin (SM) than HDL, this excimer formation was consistent with the existence of cholesterol- and SM-enriched lipid microdomains in LDL, as already suggested in model membranes of similar composition and reminiscent to the well-described “lipid rafts” in bilayer membranes. Finally, we showed that Pyr-met-Chol could stain cultured PC-3 cells via lipoprotein-mediated delivery, with a staining pattern well different to that observed with NBD-Chol non-specifically delivered to the cells.« less

Work, exercise, and space flight. 1: Operations, environment, and effects of spaceflight

NASA Technical Reports Server (NTRS)

Thornton, William

1989-01-01

The selection, training, and operations of space flight impose significant physical demands which seem to be adequately met by the existing physical training facilities and informal individual exercise programs. The professional astronaut population has, by selection, better than average health and physical capacity. The essentials of life on earth are adequately met by the spacecraft. However, as the human body adapts to weightlessness, it is compromised for the usual life on earth, but readaptation is rapid. Long term flight without countermeasures will produce major changes in the cardiovascular, respiratory, musculoskeletal and neuromuscular systems. There is strong theoretical and experimental evidence from 1-g studies and limited in-flight evidence to believe that exercise is a key counter-measure to many of these adaptations.

Target identification, lead optimization and antitumor evaluation of some new 1,2,4-triazines as c-Met kinase inhibitors.

PubMed

El-Wakil, Marwa H; Ashour, Hayam M; Saudi, Manal N; Hassan, Ahmed M; Labouta, Ibrahim M

2017-08-01

In silico target fishing approach using PharmMapper server identified c-Met kinase as the selective target for our previously synthesized compound NCI 748494/1. This approach was validated by in vitro kinase assay which showed that NCI 748494/1 possessed promising inhibitory activity against c-Met kinase (IC 50 =31.70μM). Assessment of ADMET profiling, drug-likeness, drug score as well as docking simulation for the binding pose of that compound in the active site of c-Met kinase domain revealed that NCI 748494/1 could be considered as a promising drug lead. Based on target identification and validation, it was observed that there is structure similarity between NCI 748494/1 and the reported type II c-Met kinase inhibitor BMS-777607. Optimization of our lead NCI 748494/1 furnished newly synthesized 1,2,4-triazine derivatives based on well-established structure-activity relationships, whereas three compounds namely; 4d, 7a and 8c displayed excellent in vitro cytotoxicity against three c-Met addicted cancer cell lines; A549 (lung adenocarcinoma), HT-29 (colon cancer) and MKN-45 (gastric carcinoma); with IC 50 values in the range 0.01-1.86µM. In vitro c-Met kinase assay showed 8c to possess the highest c-Met kinase inhibition profile (IC 50 =4.31µM). Docking of the active compounds in c-Met kinase active site revealed strong binding interactions comparable to the lead NCI 748494/1 and BMS-777607, suggesting that c-Met inhibition is very likely to be the mechanism of the antitumor effect of these derivatives. Copyright © 2017 Elsevier Inc. All rights reserved.

Optimal cut-off points for waist circumference in the definition of metabolic syndrome in Brazilian adults: baseline analyses of the Longitudinal Study of Adult Health (ELSA-Brasil).

PubMed

Cardinal, Thiane Ristow; Vigo, Alvaro; Duncan, Bruce Bartholow; Matos, Sheila Maria Alvim; da Fonseca, Maria de Jesus Mendes; Barreto, Sandhi Maria; Schmidt, Maria Inês

2018-01-01

Waist circumference (WC) has been incorporated in the definition of the metabolic syndrome (MetS) but the exact WC cut-off points across populations are not clear. The Joint Interim Statement (JIS) suggested possible cut-offs to different populations and ethnic groups. However, the adequacy of these cut-offs to Brazilian adults has been scarcely investigated. The objective of the study is to evaluate possible WC thresholds to be used in the definition of MetS using data from the Longitudinal Study of Adult Health (ELSA-Brasil), a multicenter cohort study of civil servants (35-74 years old) of six Brazilian cities. We analyzed baseline data from 14,893 participants (6772 men and 8121 women). A MetS was defined according to the JIS criteria, but excluding WC and thus requiring 2 of the 4 remaining elements. We used restricted cubic spline regression to graph the relationship between WC and MetS. We identified optimal cut-off points which maximized joint sensitivity and specificity (Youden's index) from Receiver Operator Characteristic Curves. We also estimated the C-statistics using logistic regression. We found no apparent threshold for WC in restricted cubic spline plots. Optimal cut-off for men was 92 cm (2 cm lower than that recommended by JIS for Caucasian/Europids or Sub-Saharan African men), but 2 cm higher than that recommended for ethnic Central and South American. For women, optimal cut-off was 86, 6 cm higher than that recommended for Caucasian/Europids and ethnic Central and South American. Optimal cut-offs did not very across age groups and most common race/color categories (except for Asian men, 87 cm). Sex-specific cut-offs for WC recommended by JIS differ from optimal cut-offs we found for adult men and women of Brazil´s most common ethnic groups.

Low sensitivity for the metabolic syndrome to detect uric acid elevations in females and non-Hispanic-black male adolescents: an analysis of NHANES 1999-2006.

PubMed

DeBoer, Mark D; Gurka, Matthew J

2012-02-01

Uric acid is tightly linked to the metabolic syndrome (MetS) and among adults higher uric acid levels are associated with future risk for diabetes, cardiovascular disease, hypertension and renal disease. Evaluate the sensitivity of MetS to identify adolescents with elevated uric acid levels on a race/ethnicity and gender-specific basis. We evaluated 3296 male and female adolescents 12-19 y participating in the National Health and Nutrition Evaluation Survey 1999-06, comprised of 67.6% non-Hispanic whites, 15.1% non-Hispanic blacks, and 17.3% Hispanics. We used a definition of MetS modified for use in adolescents and evaluated the sensitivity of a diagnosis of MetS to identify individuals with uric acid elevations (approximately the 95th percentile of uric acid by gender among normal-weight adolescents). When used as a screening test to identify individuals with uric acid elevations MetS performed more poorly among females (18.0%) than among males (37.0%) (p<0.001). Among males, MetS exhibited a lower sensitivity among non-Hispanic blacks (17.8%) compared to Hispanics (45.9%) (p<0.01) and non-Hispanic whites (37.4%) (p<0.05). There were no race/ethnicity differences in detecting elevated uric acid levels among females (non-Hispanic-white 15.5%, non-Hispanic-black 19.4%, Hispanic 26.5%, p>0.05). Current criteria to diagnose MetS exhibit racial/ethnic and gender differences in the ability to identify adolescents with elevated uric acid levels, performing poorly among non-Hispanic-black males and among females. Given emerging data regarding the ability of uric acid elevations for predicting future disease, these data may have implications regarding the use of MetS as a marker of risk among all gender and racial/ethnic groups. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

The Use of Medical Expulsive Therapy During Pregnancy: A Worldwide Perspective Among Experts.

PubMed

Lloyd, Granville L; Lim, Amy; Hamoui, Nabeel; Nakada, Stephen Y; Kielb, Stephanie J

2016-03-01

Medical expulsive therapy (MET) is a pharmacologic approach thought to augment the spontaneous passage of ureteral calculi. The usage of MET pharmacologics for presumed ureteral calculi during pregnancy has not been studied and their safety and utility are unknown. We sought to characterize the worldwide usage of MET in the setting of pregnancy with presumed ureteral calculus (P-MET), as well as factors associated with physician use. Experts in stone management were specifically sought. A nine-question survey was delivered through society-administered e-mail. Questions gathered physician's worldwide region, degree of specialization in stone disease, practice type, interval since training, and willingness to use both MET and P-MET. We assessed drugs of choice in those using P-MET and reasons for avoidance in non-P-MET users. Finally, we assessed the impact of physician-perceived medicolegal risk on usage of P-MET. Five hundred sixty-five responses were recorded. Sixty-three percent were US-based practitioners and the remaining represented a worldwide distribution. Worldwide usage of MET was 97.6%, and tamsulosin was globally preferred by over 90% of urologists. P-MET was endorsed by only 44.3%. 23.6% of European practitioners used this strategy compared with 51.1% of US physicians. Time from training and practice type did not significantly interact with adoption of P-MET; experts were less likely to use P-MET. Physician nonuse of MET during pregnancy was adverse outcome related: 76.7% reported either the fear of legal risk (52.8%) or concerns about safety (23.9%). Respondents report impressive worldwide adoption of MET. P-MET is less trusted, and fears of legal risk and safety far outweigh questions about effectiveness. The effectiveness of drugs during pregnancy-induced ureteral dilation is unknown. Still, 44% of global respondents embrace usage of this drug strategy despite a paucity of evidence supporting either safety or effectiveness during pregnancy.

Childhood metabolic syndrome, inflammation and carotid intima-media thickness. The Aboriginal Birth Cohort Study.

PubMed

Juonala, Markus; Singh, Gurmeet R; Davison, Belinda; van Schilfgaarde, Katherine; Skilton, Michael R; Sabin, Matthew A; Cheung, Michael; Sayers, Susan; Burgner, David P

2016-01-15

We evaluated whether atherosclerotic changes associated with MetS in Australian Aboriginals are reversible in childhood. In addition, we investigated whether heightened inflammation is mediating the adverse effects of MetS. The study cohort comprised of 351 children from the Aboriginal Birth Cohort Study (a longitudinal study based in the Northern Territory of Australia) aged 9-13 years at baseline examination who were followed up 6 years later. MetS was defined by at least three of the following parameters within the extreme sex- and age-specific quartile: highest quartile for waist circumference, blood pressure, triglycerides, and glucose, and lowest quartile for HDL-cholesterol. Carotid intima-media thickness (IMT) and C-reactive protein (CRP) were assessed at follow-up. Individuals with MetS at baseline or follow-up had increased carotid IMT at follow-up (mean ± SEM 539 ± 3 vs. 561 ± 8 μm, P=0.007; and 537 ± 3 vs. 567 ± 8 μm, P<0.0001 respectively). In combined analyses from baseline and follow-up studies, those individuals with MetS only at baseline had partially improved vascular status; their IMT was not significantly increased compared to those without MetS at both time-points (534 ± 3 vs. 550 ± 10 μm, P=0.09). At the follow-up examination, MetS status was associated with increased IMT levels only among individuals with CRP levels above the median (≥ 2.1mg/l) (536 ± 5 vs. 573 ± 9 μm, P<0.0001, P for interaction 0.01). MetS in childhood is associated with subclinical atherosclerosis in an Australian Aboriginal population and the effects appear to be mediated by increased inflammation. The extent of atherosclerosis was partially reduced if metabolic status improved during the follow-up. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Use of BMI as the marker of adiposity in a metabolic syndrome severity score: Derivation and validation in predicting long-term disease outcomes.

PubMed

Gurka, Matthew J; Filipp, Stephanie L; Musani, Solomon K; Sims, Mario; DeBoer, Mark D

2018-06-01

Estimates of adiposity in evaluating the metabolic syndrome (MetS) have traditionally utilized measures of waist circumference (WC), whereas body mass index (BMI) is more commonly used clinically. Our objective was to determine if a MetS severity Z-score employing BMI as its measure of adiposity (MetS-Z-BMI) would perform similarly to a WC-based score (MetS-Z-WC) in predicting future disease. To formulate the MetS-Z-BMI, we performed confirmatory factor analysis on a sex- and race/ethnicity-specific basis on MetS-related data for 6870 adult participants of the National Health and Nutrition Survey 1999-2010. We then validated this score and compared it to MetS-Z-WC in assessing correlations with future coronary heart disease (CHD) and Type 2 diabetes mellitus (T2DM) using Cox proportional hazard analysis of 13,094 participants of the Atherosclerosis Risk in Communities study and Jackson Heart Study. Loading factors, which represent the relative contribution of each component to the latent MetS factor, were lower for BMI than for WC in formulating the two respective scores (MetS-Z-BMI and MetS-Z-WC). Nevertheless, MetS-Z-BMI and MetS-Z-WC exhibited similar hazard ratios (HR) toward future disease. For each one standard-deviation-unit increase in MetS-Z-BMI, HR for CHD was 1.76 (95% confidence interval [CI]: 1.65, 1.88) and HR for T2DM was 3.39 (CI 3.16, 3.63) (both p < 0.0001). There were no meaningful differences between the MetS-Z-WC and MetS-Z-BMI scores in their associations with future CHD and T2DM. A MetS severity Z-score utilizing BMI as its measure of adiposity operated similarly to a WC-based score in predicting future CHD and T2DM, suggesting overall similarity in MetS-based risk as estimated by both measures of adiposity. This indicates potential clinical usefulness of MetS-Z-BMI in assessing and following MetS-related risk over time. Copyright © 2018 Elsevier Inc. All rights reserved.

A Comparative Analysis of the ADOS-G and ADOS-2 Algorithms: Preliminary Findings.

PubMed

Dorlack, Taylor P; Myers, Orrin B; Kodituwakku, Piyadasa W

2018-06-01

The Autism Diagnostic Observation Schedule (ADOS) is a widely utilized observational assessment tool for diagnosis of autism spectrum disorders. The original ADOS was succeeded by the ADOS-G with noted improvements. More recently, the ADOS-2 was introduced to further increase its diagnostic accuracy. Studies examining the validity of the ADOS have produced mixed findings, and pooled relationship trends between the algorithm versions are yet to be analyzed. The current review seeks to compare the relative merits of the ADOS-G and ADOS-2 algorithms, Modules 1-3. Eight studies met inclusion criteria for the review, and six were selected for paired comparisons of the sensitivity and specificity of the ADOS. Results indicate several contradictory findings, underscoring the importance of further study.

Acute physiological responses to recreational in-line skating in young adults.

PubMed

Orepic, Paula; Mikulic, Pavle; Soric, Maroje; Ruzic, Lana; Markovic, Goran

2014-01-01

We examined the physiological responses to in-line skating exercise at self-selected paces in recreationally trained adults. Seven men and 10 women performed in-line skating exercise during which oxygen uptake (VO2) and heart rate (HR) were recorded continuously. Ratings of perceived exertion (RPE) and blood lactate concentration were also obtained at the end of exercise. Furthermore, subjects' peak VO2, peak HR, RPE and gas-exchange thresholds were determined in laboratory settings. The average exercise intensity during in-line skating was 90% of peak HR, 67% of peak VO2, 84% of HR reserve and 64% of VO2 reserve. When expressed as RPE and as metabolic equivalents (METs), the average exercise intensity was 13.1 RPE and 9.4 METs. Overall, these indicators of exercise intensity categorise in-line skating at self-selected paces as a vigorous physical activity. Notably, at similar VO2 values, significantly higher HR (174 ± 16 vs. 156 ± 6 bpm; p<0.001) and RPE (13.1 ± 1.4 vs. 11.7 ± 1.4; p=0.019) were observed for in-line skating compared with treadmill running. We conclude that 1. recreational in-line skating induces physiological responses that are sufficient for improving and maintaining cardiovascular fitness in healthy adults, 2. HR- and RPE-based methods for quantifying the exercise intensity during in-line skating may overestimate the actual metabolic load and 3. the derivation of exercise prescriptions for in-line skating should be preferably based on specific (i.e. in-line skating) graded exhaustive exercise test.

A novel healthy blood pressure phenotype in the Long Life Family Study.

PubMed

Marron, Megan M; Singh, Jatinder; Boudreau, Robert M; Christensen, Kaare; Cosentino, Stephanie; Feitosa, Mary F; Minster, Ryan L; Perls, Thomas; Schupf, Nicole; Sebastiani, Paola; Ukraintseva, Svetlana; Wojczynski, Mary K; Newman, Anne B

2018-01-01

Hypertension tends to run in families and has both genetic and environmental determinants. We assessed the hypothesis that a novel healthy blood pressure (BP) phenotype is also familial and sought to identify its associated factors. We developed a healthy BP phenotype in the Long Life Family Study, a cohort of two-generation families selected for longevity. Participants from the offspring generation (n = 2211, ages 32-88) were classified as having healthy BP if their age-adjusted and sex-adjusted SBP z-score was between -1.5 and -0.5. Offspring on antihypertensive medications were classified as not having healthy BP. Families with at least two offspring (n = 419 families) were defined as meeting the healthy BP phenotype if at least two and at least 50% of their offspring had healthy BP. Among 2211 offspring, 476 (21.5%) met the healthy BP phenotype. When examining the 419 families, only 44 (10.5%) families met the criteria for the healthy BP phenotype. Both offspring and probands from families with healthy BP performed better on neuropsychological tests that place demands on complex attention and executive function when compared with offspring and probands from remaining families. Among families with the healthy BP phenotype compared with families without, a higher proportion of offspring met the American Heart Association definition of ideal cardiovascular health (10.8 versus 3.8%, respectively; driven by BP, smoking status, and BMI components). In this cohort of familial longevity, few families had a novel healthy BP phenotype in multiple members. Families with this healthy BP phenotype may represent a specific pathway to familial longevity.

Hepatocyte growth factor modulates interleukin-6 production in bone marrow derived macrophages: implications for inflammatory mediated diseases.

PubMed

Coudriet, Gina M; He, Jing; Trucco, Massimo; Mars, Wendy M; Piganelli, Jon D

2010-11-02

The generation of the pro-inflammatory cytokines IL-6, TNF-α, and IL-1β fuel the acute phase response (APR). To maintain body homeostasis, the increase of inflammatory proteins is resolved by acute phase proteins via presently unknown mechanisms. Hepatocyte growth factor (HGF) is transcribed in response to IL-6. Since IL-6 production promotes the generation of HGF and induces the APR, we posited that accumulating HGF might be a likely candidate for quelling excess inflammation under non-pathological conditions. We sought to assess the role of HGF and how it influences the regulation of inflammation utilizing a well-defined model of inflammatory activation, lipopolysaccharide (LPS)-stimulation of bone marrow derived macrophages (BMM). BMM were isolated from C57BL6 mice and were stimulated with LPS in the presence or absence of HGF. When HGF was present, there was a decrease in production of the pro-inflammatory cytokine IL-6, along with an increase in the anti-inflammatory cytokine IL-10. Altered cytokine production correlated with an increase in phosphorylated GSK3β, increased retention of the phosphorylated NFκB p65 subunit in the cytoplasm, and an enhanced interaction between CBP and phospho-CREB. These changes were a direct result of signaling through the HGF receptor, MET, as effects were reversed in the presence of a selective inhibitor of MET (SU11274) or when using BMM from macrophage-specific conditional MET knockout mice. Combined, these data provide compelling evidence that under normal circumstances, HGF acts to suppress the inflammatory response.

The Role of Echocardiography in the Optimization of Cardiac Resynchronization Therapy: Current Evidence and Future Perspectives.

PubMed

Spartalis, Michael; Tzatzaki, Eleni; Spartalis, Eleftherios; Damaskos, Christos; Athanasiou, Antonios; Livanis, Efthimios; Voudris, Vassilis

2017-01-01

Cardiac resynchronization therapy (CRT) has become a mainstay in the management of heart failure. Up to one-third of patients who received resynchronization devices do not experience the full benefits of CRT. The clinical factors influencing the likelihood to respond to the therapy are wide QRS complex, left bundle branch block, female gender, non-ischaemic cardiomyopathy (highest responders), male gender, ischaemic cardiomyopathy (moderate responders) and narrow QRS complex, non-left bundle branch block (lowest, non-responders). This review provides a conceptual description of the role of echocardiography in the optimization of CRT. A literature survey was performed using PubMed database search to gather information regarding CRT and echocardiography. A total of 70 studies met selection criteria for inclusion in the review. Echocardiography helps in the initial selection of the patients with dyssynchrony, which will benefit the most from optimal biventricular pacing and provides a guide to left ventricular (LV) lead placement during implantation. Different echocardiographic parameters have shown promise and can offer the possibility of patient selection, response prediction, lead placement optimization strategies and optimization of device configurations. LV ejection fraction along with specific electrocardiographic criteria remains the cornerstone of CRT patient selection. Echocardiography is a non-invasive, cost-effective, highly reproducible method with certain limitations and accuracy that is affected by measurement errors. Echocardiography can assist with the identification of the appropriate electromechanical substrate of CRT response and LV lead placement. The targeted approach can improve the haemodynamic response, as also the patient-specific parameters estimation.

The Role of Echocardiography in the Optimization of Cardiac Resynchronization Therapy: Current Evidence and Future Perspectives

PubMed Central

Spartalis, Michael; Tzatzaki, Eleni; Spartalis, Eleftherios; Damaskos, Christos; Athanasiou, Antonios; Livanis, Efthimios; Voudris, Vassilis

2017-01-01

Background: Cardiac resynchronization therapy (CRT) has become a mainstay in the management of heart failure. Up to one-third of patients who received resynchronization devices do not experience the full benefits of CRT. The clinical factors influencing the likelihood to respond to the therapy are wide QRS complex, left bundle branch block, female gender, non-ischaemic cardiomyopathy (highest responders), male gender, ischaemic cardiomyopathy (moderate responders) and narrow QRS complex, non-left bundle branch block (lowest, non-responders). Objective: This review provides a conceptual description of the role of echocardiography in the optimization of CRT. Method: A literature survey was performed using PubMed database search to gather information regarding CRT and echocardiography. Results: A total of 70 studies met selection criteria for inclusion in the review. Echocardiography helps in the initial selection of the patients with dyssynchrony, which will benefit the most from optimal biventricular pacing and provides a guide to left ventricular (LV) lead placement during implantation. Different echocardiographic parameters have shown promise and can offer the possibility of patient selection, response prediction, lead placement optimization strategies and optimization of device configurations. Conclusion: LV ejection fraction along with specific electrocardiographic criteria remains the cornerstone of CRT patient selection. Echocardiography is a non-invasive, cost-effective, highly reproducible method with certain limitations and accuracy that is affected by measurement errors. Echocardiography can assist with the identification of the appropriate electromechanical substrate of CRT response and LV lead placement. The targeted approach can improve the haemodynamic response, as also the patient-specific parameters estimation. PMID:29387277

Motif enrichment tool.

PubMed

Blatti, Charles; Sinha, Saurabh

2014-07-01

The Motif Enrichment Tool (MET) provides an online interface that enables users to find major transcriptional regulators of their gene sets of interest. MET searches the appropriate regulatory region around each gene and identifies which transcription factor DNA-binding specificities (motifs) are statistically overrepresented. Motif enrichment analysis is currently available for many metazoan species including human, mouse, fruit fly, planaria and flowering plants. MET also leverages high-throughput experimental data such as ChIP-seq and DNase-seq from ENCODE and ModENCODE to identify the regulatory targets of a transcription factor with greater precision. The results from MET are produced in real time and are linked to a genome browser for easy follow-up analysis. Use of the web tool is free and open to all, and there is no login requirement. ADDRESS: http://veda.cs.uiuc.edu/MET/. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

A sequential EMT-MET mechanism drives the differentiation of human embryonic stem cells towards hepatocytes.

PubMed

Li, Qiuhong; Hutchins, Andrew P; Chen, Yong; Li, Shengbiao; Shan, Yongli; Liao, Baojian; Zheng, Dejin; Shi, Xi; Li, Yinxiong; Chan, Wai-Yee; Pan, Guangjin; Wei, Shicheng; Shu, Xiaodong; Pei, Duanqing

2017-05-03

Reprogramming has been shown to involve EMT-MET; however, its role in cell differentiation is unclear. We report here that in vitro differentiation of hESCs to hepatic lineage undergoes a sequential EMT-MET with an obligatory intermediate mesenchymal phase. Gene expression analysis reveals that Activin A-induced formation of definitive endoderm (DE) accompanies a synchronous EMT mediated by autocrine TGFβ signalling followed by a MET process. Pharmacological inhibition of TGFβ signalling blocks the EMT as well as DE formation. We then identify SNAI1 as the key EMT transcriptional factor required for the specification of DE. Genetic ablation of SNAI1 in hESCs does not affect the maintenance of pluripotency or neural differentiation, but completely disrupts the formation of DE. These results reveal a critical mesenchymal phase during the acquisition of DE, highlighting a role for sequential EMT-METs in both differentiation and reprogramming.

Metformin as adjunct antituberculosis therapy.

PubMed

Singhal, Amit; Jie, Liu; Kumar, Pavanish; Hong, Gan Suay; Leow, Melvin Khee-Shing; Paleja, Bhairav; Tsenova, Liana; Kurepina, Natalia; Chen, Jinmiao; Zolezzi, Francesca; Kreiswirth, Barry; Poidinger, Michael; Chee, Cynthia; Kaplan, Gilla; Wang, Yee Tang; De Libero, Gennaro

2014-11-19

The global burden of tuberculosis (TB) morbidity and mortality remains immense. A potential new approach to TB therapy is to augment protective host immune responses. We report that the antidiabetic drug metformin (MET) reduces the intracellular growth of Mycobacterium tuberculosis (Mtb) in an AMPK (adenosine monophosphate-activated protein kinase)-dependent manner. MET controls the growth of drug-resistant Mtb strains, increases production of mitochondrial reactive oxygen species, and facilitates phagosome-lysosome fusion. In Mtb-infected mice, use of MET ameliorated lung pathology, reduced chronic inflammation, and enhanced the specific immune response and the efficacy of conventional TB drugs. Moreover, in two separate human cohorts, MET treatment was associated with improved control of Mtb infection and decreased disease severity. Collectively, these data indicate that MET is a promising candidate host-adjunctive therapy for improving the effective treatment of TB. Copyright © 2014, American Association for the Advancement of Science.

The selective orexin receptor 1 antagonist ACT-335827 in a rat model of diet-induced obesity associated with metabolic syndrome.

PubMed

Steiner, Michel A; Sciarretta, Carla; Pasquali, Anne; Jenck, Francois

2013-01-01

The orexin system regulates feeding, nutrient metabolism and energy homeostasis. Acute pharmacological blockade of orexin receptor 1 (OXR-1) in rodents induces satiety and reduces normal and palatable food intake. Genetic OXR-1 deletion in mice improves hyperglycemia under high-fat (HF) diet conditions. Here we investigated the effects of chronic treatment with the novel selective OXR-1 antagonist ACT-335827 in a rat model of diet-induced obesity (DIO) associated with metabolic syndrome (MetS). Rats were fed either standard chow (SC) or a cafeteria (CAF) diet comprised of intermittent human snacks and a constant free choice between a HF/sweet (HF/S) diet and SC for 13 weeks. Thereafter the SC group was treated with vehicle (for 4 weeks) and the CAF group was divided into a vehicle and an ACT-335827 treatment group. Energy and water intake, food preference, and indicators of MetS (abdominal obesity, glucose homeostasis, plasma lipids, and blood pressure) were monitored. Hippocampus-dependent memory, which can be impaired by DIO, was assessed. CAF diet fed rats treated with ACT-335827 consumed less of the HF/S diet and more of the SC, but did not change their snack or total kcal intake compared to vehicle-treated rats. ACT-335827 increased water intake and the high-density lipoprotein associated cholesterol proportion of total circulating cholesterol. ACT-335827 slightly increased body weight gain (4% vs. controls) and feed efficiency in the absence of hyperphagia. These effects were not associated with significant changes in the elevated fasting glucose and triglyceride (TG) plasma levels, glucose intolerance, elevated blood pressure, and adiposity due to CAF diet consumption. Neither CAF diet consumption alone nor ACT-335827 affected memory. In conclusion, the main metabolic characteristics associated with DIO and MetS in rats remained unaffected by chronic ACT-335827 treatment, suggesting that pharmacological OXR-1 blockade has minimal impact in this model.

Population-based family case-control proband study on familial aggregation of metabolic syndrome: finding from Taiwanese people involved in Keelung community-based integrated screening (KCIS no. 5).

PubMed

Chiu, Yueh-Hsia; Lin, Wen-Yuan; Wang, Po-En; Chen, Yao-Der; Wang, Ting-Ting; Warwick, Jane; Chen, Tony Hsiu-Hsi

2007-03-01

A population-based case-control proband study was undertaken to elucidate familial aggregation, independent environmental factors, and the interaction between them. A total of 7308 metabolic syndrome (MET-S) cases were identified from the Keelung community-based integrated screening programme between 1999 and 2002. The study has a case-control/family sampling design. A total of 1417 case probands were randomly selected from 3225 metabolic syndrome cases and the corresponding 2458 controls selected from 16,519 subjects without metabolic syndrome by matching on sex, age (+/-3 years) and place of residence. The generalized estimation equation model was used to estimate odds ratios and corresponding 95% confidence intervals. The risk for having metabolic syndrome among family members for cases versus control probands was 1.56-fold (1.29-1.89) after controlling for significant environmental factors. Higher risk of metabolic syndrome was found in parents than spouse. Low education against high education had 2.06-fold (1.36-3.13) risk for metabolic syndrome. Betel quid chewing was positively associated with the risk of MET-S, with 1.99-fold (1.13-3.53) risk for 1-9 pieces and 1.76-fold (0.96-3.23) risk for >or=10 pieces compared with non-chewer. Moderate and high intensity of non-occupational exercise led to 21.0% (OR=0.79 (0.63-0.98)) and 26.0% (OR=0.74 (0.59-0.94)) reduction in the risk for metabolic syndrome, respectively. The frequent consumption of vegetable reduced 24.0% (OR=0.76 (0.62-0.92)) risk for MET-S. The frequent consumption of coffee was associated the increased risk for metabolic syndrome (OR=1.32 (1.07-1.64)). The present study confirmed the risk of metabolic syndrome not only has the tendency towards familial aggregation but is affected by independent effect of environmental or individual correlates.

Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 2.

PubMed

McBride, Christopher; Cheruvallath, Zacharia; Komandla, Mallareddy; Tang, Mingnam; Farrell, Pamela; Lawson, J David; Vanderpool, Darin; Wu, Yiqin; Dougan, Douglas R; Plonowski, Artur; Holub, Corine; Larson, Chris

2016-06-15

Methionine aminopeptidase-2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. This step is required before they will fold or function correctly. Pre-clinical and clinical studies with a MetAP2 inhibitor suggest that they could be used as a novel treatment for obesity. Herein we describe the discovery of a series of pyrazolo[4,3-b]indoles as reversible MetAP2 inhibitors. A fragment-based drug discovery (FBDD) approach was used, beginning with the screening of fragment libraries to generate hits with high ligand-efficiency (LE). An indazole core was selected for further elaboration, guided by structural information. SAR from the indazole series led to the design of a pyrazolo[4,3-b]indole core and accelerated knowledge-based fragment growth resulted in potent and efficient MetAP2 inhibitors, which have shown robust and sustainable body weight loss in DIO mice when dosed orally. Copyright © 2016 Elsevier Ltd. All rights reserved.

[How to reduce health inequities by targeting social determinants: the role of the health sector in Mexico].

PubMed

Martínez Valle, Adolfo; Terrazas, Paulina; Alvarez, Fernando

2014-04-01

To study lines of action implemented in Mexico by the health sector from 2007 to 2012 in order to combat health inequities by targeting social determinants. To contribute to better understanding and knowledge of how health system inequalities in the Region of the Americas can be reduced. To formulate recommendations for designing a future public policy agenda to address the social determinants associated with health inequities in Mexico. The policies and programs established in the National Health Program (PRONASA) 2007 - 2012 were reviewed, and those that met four criteria were selected: i) they affected the social determinants of health (SDH); ii) they developed specific lines of action aimed at reducing health inequities; iii) they set concrete goals; and iv) they had been evaluated to determine whether those goals had been met. Three programs were selected: Seguro Popular, Programa de Desarrollo Humano Oportunidades (PDHO), and Caravanas de la Salud. Once each program's specific lines of action targeting SDH had been identified, the monitoring and evaluation indicators established in PRONASA 2007 - 2012, along with other available evaluations and empirical evidence, were used to measure the extent to which the goals were met. The findings showed that Seguro Popular had had a positive impact in terms of the financial protection of lower-income households. Moreover, the reduction in the gap between workers covered by the social security system and those who were not was more evident. By reducing poverty among its beneficiaries, the PDHO also managed to reduce health inequities. The indicators for Caravanas de la Salud, on the other hand, did not show statistically significant differences between the control localities and the localities covered by the program, except in the case of Pap tests. These findings have important public policy implications for designing an agenda that promotes continued targeting of SDH and heightening its impact in terms of reducing inequities. Guaranteeing the effective exercise of social rights, without socioeconomic, employment, ethnic, or gender-based exclusion, will be key. Action to provide comprehensive, inclusive, equitable, effective, and quality coverage, supported by a preventive and remedial model of primary health care, are recommended. Strategies should be centered on primary health services, because at that level, more comprehensive care focusing on the person rather than the disease can be provided. It will also be necessary to include periodic monitoring and evaluation phases to offer the comprehensive social protection system scientific armor and guarantee its effectiveness.

Dysautonomia Rating Scales in Parkinson’s Disease: Sialorrhea, Dysphagia, and Constipation—Critique and Recommendations by Movement Disorders Task Force on Rating Scales for Parkinson’s Disease

PubMed Central

Evatt, Marian L.; Chaudhuri, K. Ray; Chou, Kelvin L.; Cubo, Ester; Hinson, Vanessa; Kompoliti, Katie; Yang, Chengwu; Poewe, Werner; Rascol, Olivier; Sampaio, Cristina; Stebbins, Glenn T.; Goetz, Christopher G.

2015-01-01

Upper and lower gastrointestinal dysautonomia symptoms (GIDS)—sialorrhea, dysphagia, and constipation are common in Parkinson’s disease (PD) and often socially as well as physically disabling for patients. Available invasive quantitative measures for assessing these symptoms and their response to therapy are time-consuming, require specialized equipment, can cause patient discomfort and present patients with risk. The Movement Disorders Society commissioned a task force to assess available clinical rating scales, critique their clinimetric properties, and make recommendations regarding their clinical utility. Six clinical researchers and a biostatistician systematically searched the literature for scales of sialorrhea, dysphagia, and constipation, evaluated the scales’ previous use, performance parameters, and quality of validation data (if available). A scale was designated “Recommended” if the scale was used in clinical studies beyond the group that developed it, has been specifically used in PD reports, and clinimetric studies have established that it is a valid, reliable, and sensitive. “Suggested” scales met at least part of the above criteria, but fell short of meeting all. Based on the systematic review, scales for individual symptoms of sialorrhea, dysphagia, and constipation were identified along with three global scales that include these symptoms in the context of assessing dysautonomia or nonmotor symptoms. Three sialorrhea scales met criteria for Suggested: Drooling Severity and Frequency Scale (DSFS), Drooling Rating Scale, and Sialorrhea Clinical Scale for PD (SCS-PD). Two dysphagia scales, the Swallowing Disturbance Questionnaire (SDQ) and Dysphagia-Specific Quality of Life (SWAL-QOL), met criteria for Suggested. Although Rome III constipation module is widely accepted in the gastroenterology community, and the earlier version from the Rome II criteria has been used in a single study of PD patients, neither met criteria for Suggested or Recommended. Among the global scales, the Scales for Outcomes in PD-Autonomic (SCOPA-AUT) and Nonmotor Symptoms Questionnaire for PD (NMSQuest) both met criteria for Recommended, and the Nonmotor Symptoms Scale (NMSS) met criteria for Suggested; however, none specifically focuses on the target gastrointestinal symptoms (sialorrhea, dysphagia, and constipation) of this report. A very small number of rating scales have been applied to studies of gastrointestinal-related dysautonomia in PD. Only two scales met “Recommended” criteria and neither focuses specifically on the symptoms of sialorrhea, dysphagia, and constipation. Further scale testing in PD among the scales that focus on these symptoms is warranted, and no new scales are needed until the available scales are fully tested clinimetrically. PMID:19205066

Dysautonomia rating scales in Parkinson's disease: sialorrhea, dysphagia, and constipation--critique and recommendations by movement disorders task force on rating scales for Parkinson's disease.

PubMed

Evatt, Marian L; Chaudhuri, K Ray; Chou, Kelvin L; Cubo, Ester; Hinson, Vanessa; Kompoliti, Katie; Yang, Chengwu; Poewe, Werner; Rascol, Olivier; Sampaio, Cristina; Stebbins, Glenn T; Goetz, Christopher G

2009-04-15

Upper and lower gastrointestinal dysautonomia symptoms (GIDS)--sialorrhea, dysphagia, and constipation are common in Parkinson's disease (PD) and often socially as well as physically disabling for patients. Available invasive quantitative measures for assessing these symptoms and their response to therapy are time-consuming, require specialized equipment, can cause patient discomfort and present patients with risk. The Movement Disorders Society commissioned a task force to assess available clinical rating scales, critique their clinimetric properties, and make recommendations regarding their clinical utility. Six clinical researchers and a biostatistician systematically searched the literature for scales of sialorrhea, dysphagia, and constipation, evaluated the scales' previous use, performance parameters, and quality of validation data (if available). A scale was designated "Recommended" if the scale was used in clinical studies beyond the group that developed it, has been specifically used in PD reports, and clinimetric studies have established that it is a valid, reliable, and sensitive. "Suggested" scales met at least part of the above criteria, but fell short of meeting all. Based on the systematic review, scales for individual symptoms of sialorrhea, dysphagia, and constipation were identified along with three global scales that include these symptoms in the context of assessing dysautonomia or nonmotor symptoms. Three sialorrhea scales met criteria for Suggested: Drooling Severity and Frequency Scale (DSFS), Drooling Rating Scale, and Sialorrhea Clinical Scale for PD (SCS-PD). Two dysphagia scales, the Swallowing Disturbance Questionnaire (SDQ) and Dysphagia-Specific Quality of Life (SWAL-QOL), met criteria for Suggested. Although Rome III constipation module is widely accepted in the gastroenterology community, and the earlier version from the Rome II criteria has been used in a single study of PD patients, neither met criteria for Suggested or Recommended. Among the global scales, the Scales for Outcomes in PD-Autonomic (SCOPA-AUT) and Nonmotor Symptoms Questionnaire for PD (NMSQuest) both met criteria for Recommended, and the Nonmotor Symptoms Scale (NMSS) met criteria for Suggested; however, none specifically focuses on the target gastrointestinal symptoms (sialorrhea, dysphagia, and constipation) of this report. A very small number of rating scales have been applied to studies of gastrointestinal-related dysautonomia in PD. Only two scales met "Recommended" criteria and neither focuses specifically on the symptoms of sialorrhea, dysphagia, and constipation. Further scale testing in PD among the scales that focus on these symptoms is warranted, and no new scales are needed until the available scales are fully tested clinimetrically.

Variant BDNF (Val66Met) polymorphism contributes to developmental and estrous-stage-specific expression of anxiety-like behavior in female mice

PubMed Central

Bath, Kevin G.; Chuang, Jocelyn; Spencer-Segal, Joanna L.; Amso, Dima; Altemus, Margaret; McEwen, Bruce S.; Lee, Francis S.

2012-01-01

Background Most anxiety and depressive disorders are twice as common in women compared to men and the sex difference in prevalence typically emerges during adolescence. Hormonal changes across the menstrual cycle and during the postpartum and peri-menopausal periods are associated with increased risk for anxiety and depression symptoms. In humans and animals, reduced brain derived neurotrophic factor (BDNF) has been associated with increased expression of affective pathology. Recently, a single nucleotide polymorphism (SNP) in the BDNF gene (BDNF Val66Met), which reduces BDNF bioavailability, has been identified in humans and associated with a variety of neuropsychiatric disorders. Although BDNF expression can be directly influenced by estrogen and progesterone, the potential impact of the BDNF Val66Met SNP on sensitivity to reproductive hormone changes remains an open question. Approach As a predictive model, we used female mice in which the human SNP (BDNF Val66Met) was inserted into the mouse BDNF gene. Using standard behavioral paradigms, we tested the impact of this SNP on age and estrous-cycle specific expression of anxiety-like behaviors. Results Mice homozygous for the BDNF Val66Met SNP begin to exhibit increased anxiety-like behaviors over prepubertal and early adult development, show significant fluctuations in anxiety-like behaviors over the estrous cycle, and as adults differ from wild-type mice by showing significant fluctuations in anxiety-like behaviors over the estrous cycle, specifically more anxiety-like behaviors during the estrus phase. Conclusions These findings have implications regarding the potential role of this SNP in contributing to developmental and reproductive hormone-dependent changes in affective disorders in humans. PMID:22552045

Designing a more efficient, effective and safe Medical Emergency Team (MET) service using data analysis

PubMed Central

Bilgrami, Irma; Bain, Christopher; Webb, Geoffrey I.; Orosz, Judit; Pilcher, David

2017-01-01

Introduction Hospitals have seen a rise in Medical Emergency Team (MET) reviews. We hypothesised that the commonest MET calls result in similar treatments. Our aim was to design a pre-emptive management algorithm that allowed direct institution of treatment to patients without having to wait for attendance of the MET team and to model its potential impact on MET call incidence and patient outcomes. Methods Data was extracted for all MET calls from the hospital database. Association rule data mining techniques were used to identify the most common combinations of MET call causes, outcomes and therapies. Results There were 13,656 MET calls during the 34-month study period in 7936 patients. The most common MET call was for hypotension [31%, (2459/7936)]. These MET calls were strongly associated with the immediate administration of intra-venous fluid (70% [1714/2459] v 13% [739/5477] p<0.001), unless the patient was located on a respiratory ward (adjusted OR 0.41 [95%CI 0.25–0.67] p<0.001), had a cardiac cause for admission (adjusted OR 0.61 [95%CI 0.50–0.75] p<0.001) or was under the care of the heart failure team (adjusted OR 0.29 [95%CI 0.19–0.42] p<0.001). Modelling the effect of a pre-emptive management algorithm for immediate fluid administration without MET activation on data from a test period of 24 months following the study period, suggested it would lead to a 68.7% (2541/3697) reduction in MET calls for hypotension and a 19.6% (2541/12938) reduction in total METs without adverse effects on patients. Conclusion Routinely collected data and analytic techniques can be used to develop a pre-emptive management algorithm to administer intravenous fluid therapy to a specific group of hypotensive patients without the need to initiate a MET call. This could both lead to earlier treatment for the patient and less total MET calls. PMID:29281665

Acid sphingomyelinase is required for cell surface presentation of Met receptor tyrosine kinase in cancer cells

PubMed Central

Zhu, Linyu; Xiong, Xiahui; Kim, Yongsoon; Okada, Naomi; Lu, Fei; Zhang, Hui

2016-01-01

ABSTRACT Receptor tyrosine kinases (RTKs) are embedded in the lipid bilayer of the plasma membrane, but the specific roles of various lipids in cell signaling remain largely uncharacterized. We have previously found that acid sphingomyelinase (ASM; also known as SMPD1) regulates the conserved DAF-2 (the ortholog IGF-1R in mammals) RTK signaling pathway in Caenorhabditis elegans. How ASM and its catalytic products, ceramides, control RTK signaling pathways remain unclear. Here, we report that ASM regulates the homeostasis of Met, an RTK that is frequently overexpressed in various cancers. Inactivation of ASM led to a rapid loss of Met from the plasma membrane, reduced Met phosphorylation and activation, and induced Met accumulation in the trans-Golgi network (TGN). However, trafficking of integrin β3 and vesicular stomatitis virus glycoprotein (VSVG) was largely unaffected. Knockdown of syntaxin 6 (STX6) also blocked the Golgi exit of Met. Depletion of either ASM or STX6 led to aberrant trafficking of Met to lysosomes, promoting its degradation. Our studies reveal that ASM and ceramides, together with STX6 and cholesterol, constitute a new regulatory mechanism for the exit of Met from the Golgi during its biosynthetic route, which is used to rapidly replenish and regulate the plasma membrane levels of Met in various cancer cells. PMID:27802163

BDNF Val66Met polymorphism modulates the effect of loneliness on white matter microstructure in young adults.

PubMed

Meng, Jie; Hao, Lei; Wei, Dongtao; Sun, Jiangzhou; Li, Yu; Qiu, Jiang

2017-12-01

Loneliness is a common experience. Susceptibility to loneliness is a stable trait and is heritable. Previous studies have suggested that loneliness may impact regional gray matter density and brain activation to social stimuli, but its relation to white matter structure and how it may interact with genetic factors remains unclear. In this study, we investigated whether and how a common polymorphism (Val66Met) in the brain-derived neurotrophic factor gene modulated the association between loneliness and white matter microstructure in 162 young adults. The tract-based spatial statistics analyses revealed that the relationships between loneliness and white matter microstructures were significantly different between Val/Met heterozygotes and Val/Val homozygotes. Specifically, loneliness was significantly correlated with reduced fractional anisotropy and increased radial diffusivity in widespread white matter fibers within Val/Met heterozygotes. It was also significantly correlated with increased radial diffusivity in Met/Met genotypes but showed no significant association with white matter measures in Val/Val genotypes. Furthermore, the associations between loneliness and fractional anisotropy (or radial diffusivity) in Val/Met heterozygotes turned out to be global effects. These results provide evidence that loneliness may interact with the BDNF Val66Met polymorphism to shape the microstructures of white matter, and the Val/Met heterozygotes may be more susceptible to social environment. Copyright © 2017 Elsevier B.V. All rights reserved.

Fructose consumption reduces hippocampal synaptic plasticity underlying cognitive performance

PubMed Central

Cisternas, Pedro; Salazar, Paulina; Serrano, Felipe G.; Montecinos-Oliva, Carla; Arredondo, Sebastián B.; Varela-Nallar, Lorena; Barja, Salesa; Vio, Carlos P.; Gomez-Pinilla, Fernando; Inestrosa, Nibaldo C.

2017-01-01

Metabolic syndrome (MetS) is a global epidemic, which involves a spectrum of metabolic disorders comprising diabetes and obesity. The impact of MetS on the brain is becoming to be a concern, however, the poor understanding of mechanisms involved has limited the development of therapeutic strategies. We induced a MetS-like condition by exposing mice to fructose feeding for 7 weeks. There was a dramatic deterioration in the capacity of the hippocampus to sustain synaptic plasticity in the forms of long-term potentiation (LTP) and long-term depression (LTD). Mice exposed to fructose showed a reduction in the number of contact zones and the size of postsynaptic densities (PSDs) in the hippocampus, as well as a decrease in hippocampal neurogenesis. There was an increase in lipid peroxidation likely associated with a deficiency in plasma membrane excitability. Consistent with an overall hippocampal dysfunction, there was a subsequent decrease in hippocampal dependent learning and memory performance, i.e., spatial learning and episodic memory. Most of the pathological sequel of MetS in the brain was reversed three month after discontinue fructose feeding. These results are novel to show that MetS triggers a cascade of molecular events, which disrupt hippocampal functional plasticity, and specific aspects of learning and memory function. The overall information raises concerns about the risk imposed by excessive fructose consumption on the pathology of neurological disorders. PMID:26300486

Epigenetic Upregulation of HGF and c-Met Drives Metastasis in Hepatocellular Carcinoma

PubMed Central

Ogunwobi, Olorunseun O.; Puszyk, William; Dong, Hui-Jia; Liu, Chen

2013-01-01

Hepatocyte growth factor (HGF) and its receptor, c-Met, are important regulators of growth and differentiation of healthy hepatocytes. However, upregulation of HGF and c-Met have been associated with tumor progression and metastasis in hepatocellular carcinoma (HCC). Hematogenous dissemination is the most common route for cancer metastasis, but the role of HGF and c-Met in circulating tumor cells (CTCs) is unknown. We have isolated and established a circulating tumor cell line from the peripheral blood of a mouse HCC model. Our studies show that these CTCs have increased expression of HGF and c-Met in comparison to the primary tumor cells. The CTCs display phenotypic evidence of epithelial-mesenchymal transition (EMT) and the EMT appears to be inducible by HGF. Epigenetic analysis of the c-Met promoter identified significant loss of DNA methylation in CTCs which correlated with overexpression of c-Met and increased expression of HGF. Six specific CpG sites of c-Met promoter demethylation were identified. CTCs show significantly increased tumorigenicity and metastatic potential in a novel orthotopic syngeneic model of metastatic HCC. We conclude that during hematogenous dissemination in HCC, CTCs undergo EMT under the influence of increased HGF. This process also involves up regulation of c-Met via promoter demethylation at 6 CpG sites. Consequently, targeting HGF and c-Met expression by CTCs may be a novel non-invasive approach with potential clinical applications in HCC management. PMID:23723997

Description of a healthy lifestyle intervention for people with serious mental illness taking second-generation antipsychotics.

PubMed

Park, Tanya; Usher, Kim; Foster, Kim

2011-12-01

Weight gain and obesity has reached epidemic proportions, with the prevalence of metabolic syndrome (MetS) reaching 20-25% of the global population. MetS is a cluster of metabolic abnormalities, including weight gain, associated with an increased risk of cardiovascular disease, diabetes, and stroke. While individuals in the general population are at risk of physical conditions, such as MetS, people with mental illness are at even higher risk. The increased incidence of MetS for people with serious mental illness has been linked to the use of second-generation antipsychotic medication. This paper describes the content, structure, and development of 'Passport 4 Life', a healthy lifestyle intervention to maintain weight and prevent further weight gain for people with serious mental illness. While there are a number of diet and lifestyle programmes available for the general population, Passport 4 Life was specifically designed as an intervention to address the needs of people with serious mental illness taking second-generation antipsychotics. Passport 4 Life comprises 12 weekly group sessions that include the concepts and spirit of motivational interviewing, nutrition, and exercise education, combined with weekly exercise activity. © 2011 The Authors. International Journal of Mental Health Nursing © 2011 Australian College of Mental Health Nurses Inc.

Biochemical Assessment of Bone Health in Working Obese Egyptian Females with Metabolic Syndrome; the Effect of Weight Loss by Natural Dietary Therapies

PubMed Central

Moaty, Maha I. A.; Fouad, Suzanne; Shebini, Salwa M. El; Kazem, Yusr I.; Tapozada, Salwa T.

2015-01-01

AIM: To investigate the relation between bone parameters and the metabolic syndrome criteria, before and after the administration of two different natural dietary supplements in middle aged working obese Egyptian women suffering from metabolic syndrome (MetS). SUBJECTS AND METHODS: Fifty eight middle aged obese female volunteers suffering from metabolic syndrome were divided into two groups. During the first period, group (A) consumed a low caloric diet and nutritional supplement consisting of doum flour biscuits, while group (B) consumed whole meal wheat flour biscuit with the same instructions. During the second period, both supplements were omitted. Assessment of blood pressure, relevant anthropometric parameters, lipid accumulation product, fasting blood glucose, uric acid, 25 hydroxy vitamin D (25 (OH) D), parathyroid hormone (PTH) and bone-specific alkaline phosphatase were performed. RESULTS: Data showed that although both supplements improved the MetS criteria and the bone health parameters, the supplement containing the doum flour proved to be more effective. CONCLUSION: These results confirm the benefit of doum in improving bone health parameter [25 (OH) D/PTH axis] in the MetS patients, beside the MetS criteria. So, we can conclude that natural effective supplements lead towards the optimization of biochemical parameters in favor of a healthy outcome. PMID:27275291

Met receptor signaling is required for sensory nerve development and HGF promotes axonal growth and survival of sensory neurons

PubMed Central

Maina, Flavio; Hilton, Mark C.; Ponzetto, Carola; Davies, Alun M.; Klein, Rüdiger

1997-01-01

The development of the nervous system is a dynamic process during which factors act in an instructive fashion to direct the differentiation and survival of neurons, and to induce axonal outgrowth, guidance to, and terminal branching within the target tissue. Here we report that mice expressing signaling mutants of the hepatocyte growth factor (HGF) receptor, the Met tyrosine kinase, show a striking reduction of sensory nerves innervating the skin of the limbs and thorax, implicating the HGF/Met system in sensory neuron development. Using in vitro assays, we find that HGF cooperates with nerve growth factor (NGF) to enhance axonal outgrowth from cultured dorsal root ganglion (DRG) neurons. HGF also enhances the neurotrophic activities of NGF in vitro, and Met receptor signaling is required for the survival of a proportion of DRG neurons in vivo. This synergism is specific for NGF but not for the related neurotrophins BDNF and NT3. By using a mild signaling mutant of Met, we have demonstrated previously that Met requires signaling via the adapter molecule Grb2 to induce proliferation of myoblasts. In contrast, the actions of HGF on sensory neurons are mediated by Met effectors distinct from Grb2. Our findings demonstrate a requirement for Met signaling in neurons during development. PMID:9407027

Characterization of the Drosophila Methoprene -tolerant gene product. Juvenile hormone binding and ligand-dependent gene regulation.

PubMed

Miura, Ken; Oda, Masahito; Makita, Sumiko; Chinzei, Yasuo

2005-03-01

Juvenile hormones (JHs) of insects are sesquiterpenoids that regulate a great diversity of processes in development and reproduction. As yet the molecular modes of action of JH are poorly understood. The Methoprene-tolerant (Met) gene of Drosophila melanogaster has been found to be responsible for resistance to a JH analogue (JHA) insecticide, methoprene. Previous studies on Met have implicated its involvement in JH signaling, although direct evidence is lacking. We have now examined the product of Met (MET) in terms of its binding to JH and ligand-dependent gene regulation. In vitro synthesized MET directly bound to JH III with high affinity (Kd = 5.3 +/- 1.5 nm, mean +/- SD), consistent with the physiological JH concentration. In transient transfection assays using Drosophila S2 cells the yeast GAL4-DNA binding domain fused to MET exerted JH- or JHA-dependent activation of a reporter gene. Activation of the reporter gene was highly JH- or JHA-specific with the order of effectiveness: JH III > JH II > JH I > methoprene; compounds which are only structurally related to JH or JHA did not induce any activation. Localization of MET in the S2 cells was nuclear irrespective of the presence or absence of JH. These results suggest that MET may function as a JH-dependent transcription factor.

Who gets afraid in the MRI-scanner? Neurogenetics of state-anxiety changes during an fMRI experiment.

PubMed

Mutschler, Isabella; Wieckhorst, Birgit; Meyer, Andrea H; Schweizer, Tina; Klarhöfer, Markus; Wilhelm, Frank H; Seifritz, Erich; Ball, Tonio

2014-11-07

Experiments using functional magnetic resonance imaging (fMRI) play a fundamental role in affective neuroscience. When placed in an MR scanner, some volunteers feel safe and relaxed in this situation, while others experience uneasiness and fear. Little is known about the basis and consequences of such inter-individually different responses to the general experimental fMRI setting. In this study emotional stimuli were presented during fMRI and subjects' state-anxiety was assessed at the onset and end of the experiment while they were within the scanner. We show that Val/Val but neither Met/Met nor Val/Met carriers of the catechol-O-methyltransferase (COMT) Val(158)Met polymorphism-a prime candidate for anxiety vulnerability-became significantly more anxious during the fMRI experiment (N=97 females: 24 Val/Val, 51 Val/Met, and 22 Met/Met). Met carriers demonstrated brain responses with increased stability over time in the right parietal cortex and significantly better cognitive performances likely mediated by lower levels of anxiety. Val/Val, Val/Met and Met/Met did not significantly differ in state-anxiety at the beginning of the experiment. The exposure of a control group (N=56 females) to the same experiment outside the scanner did not cause a significant increase in state-anxiety, suggesting that the increase we observe in the fMRI experiment may be specific to the fMRI setting. Our findings reveal that genetics may play an important role in shaping inter-individual different emotional, cognitive and neuronal responses during fMRI experiments. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Enquire within: cultural evolution and cognitive science.

PubMed

Heyes, Cecilia

2018-04-05

Cultural evolution and cognitive science need each other. Cultural evolution needs cognitive science to find out whether the conditions necessary for Darwinian evolution are met in the cultural domain. Cognitive science needs cultural evolution to explain the origins of distinctively human cognitive processes. Focusing on the first question, I argue that cultural evolutionists can get empirical traction on third-way cultural selection by rooting the distinction between replication and reconstruction, two modes of cultural inheritance, in the distinction between System 1 and System 2 cognitive processes. This move suggests that cultural epidemiologists are right in thinking that replication has higher fidelity than reconstruction, and replication processes are not genetic adaptations for culture, but wrong to assume that replication is rare. If replication is not rare, an important requirement for third-way cultural selection, one-shot fidelity , is likely to be met. However, there are other requirements, overlooked by dual-inheritance theorists when they conflate strong (Darwinian) and weak (choice) senses of 'cultural selection', including dumb choices and recurrent fidelity In a second excursion into cognitive science, I argue that these requirements can be met by metacognitive social learning strategies , and trace the origins of these distinctively human cognitive processes to cultural evolution. Like other forms of cultural learning, they are not cognitive instincts but cognitive gadgets.This article is part of the theme issue 'Bridging cultural gaps: interdisciplinary studies in human cultural evolution'. © 2018 The Author(s).

77 FR 33786 - NRC Enforcement Policy Revision

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-07

... methods: Federal Rulemaking Web site: Go to http://www.regulations.gov and search for Docket ID NRC-2011... search, select ``ADAMS Public Documents'' and then select ``Begin Web- based ADAMS Search.'' For problems... either 2.3.2.a. or b. must be met for the disposition of a violation as an NCV.'' The following new...

Potent and selective agonists of alpha-melanotropin (alphaMSH) action at human melanocortin receptor 5; linear analogs of alpha-melanotropin.

PubMed

Bednarek, Maria A; MacNeil, Tanya; Tang, Rui; Fong, Tung M; Cabello, M Angeles; Maroto, Marta; Teran, Ana

2007-05-01

Alpha-melanotropin, Ac-Ser(1)-Tyr-Ser-Met-Glu-His(6)-Phe(7)-Arg(8)-Trp(9)-Gly-Lys-Pro-Val(13)-NH(2)(1), is a non-selective endogenous agonist for the melanocortin receptor 5; the receptor present in various peripheral tissues and in the brain, cortex and cerebellum. Most of the synthetic analogs of alphaMSH, including a broadly used and more potent the NDP-alphaMSH peptide, Ac-Ser(1)-Tyr-Ser-Nle(4)-Glu-His(6)-D-Phe(7)-Arg(8)-Trp(9)-Gly-Lys-Pro-Val(13)-NH(2), are also not particularly selective for MC5R. To elucidate physiological functions of the melanocortin receptor 5 in rodents and humans, the receptor subtype selective research tools are needed. We report herein syntheses and pharmacological evaluation in vitro of several analogs of NDP-alphaMSH which are highly potent and specific agonists for the human MC5R. The new linear peptides, of structures and solubility properties similar to those of the endogenous ligand alphaMSH, are exemplified by compound 7, Ac-Ser(1)-Tyr-Ser-Met-Glu-Oic(6)-D-4,4'-Bip(7)-Pip(8)-Trp(9)-Gly-Lys-Pro-Val(13)-NH(2) (Oic: octahydroindole-2-COOH, 4,4'-Bip: 4,4'-biphenylalanine, Pip: pipecolic acid), shortly NODBP-alphaMSH, which has an IC(50)=0.74 nM (binding assay) and EC(50)=0.41 (cAMP production assay) at hMC5R nM and greater than 3500-fold selectivity with respect to the melanocortin receptors 1b, 3 and 4. A shorter peptide derived from NODBP-alphaMSH: Ac-Nle-Glu-Oic(6)-D-4,4'-Bip(7)-Pip(8)-Trp(9) -NH(2) (17) was measured to be an agonist only 10-fold less potent at hMC5R than the full length parent peptide. In the structure of this smaller analog, the Nle-Glu-Oic(6)-D-4,4'-Bip(7)-Pip(8) segment was found to be critical for high agonist potency, while the C-terminal Trp(9) residue was shown to be required for high hMC5R selectivity versus hMC1b,3,4R.

Characteristics of time-activity curves obtained from dynamic 11C-methionine PET in common primary brain tumors.

PubMed

Nomura, Yuichi; Asano, Yoshitaka; Shinoda, Jun; Yano, Hirohito; Ikegame, Yuka; Kawasaki, Tomohiro; Nakayama, Noriyuki; Maruyama, Takashi; Muragaki, Yoshihiro; Iwama, Toru

2018-07-01

The aim of this study was to assess whether dynamic PET with 11 C-methionine (MET) (MET-PET) is useful in the diagnosis of brain tumors. One hundred sixty patients with brain tumors (139 gliomas, 9 meningiomas, 4 hemangioblastomas and 8 primary central nervous system lymphomas [PCNSL]) underwent dynamic MET-PET with a 3-dimensional acquisition mode, and the maximum tumor MET-standardized uptake value (MET-SUV) was measured consecutively to construct a time-activity curve (TAC). Furthermore, receiver operating characteristic (ROC) curves were generated from the time-to-peak (TTP) and the slope of the curve in the late phase (SLOPE). The TAC patterns of MET-SUVs (MET-TACs) could be divided into four characteristic types when MET dynamics were analyzed by dividing the MET-TAC into three phases. MET-SUVs were significantly higher in early and late phases in glioblastoma compared to anaplastic astrocytoma, diffuse astrocytoma and the normal frontal cortex (P < 0.05). The SLOPE in the late phase was significantly lower in tumors that included an oligodendroglial component compared to astrocytic tumors (P < 0.001). When we set the cutoff of the SLOPE in the late phase to - 0.04 h -1 for the differentiation of tumors that included an oligodendroglial component from astrocytic tumors, the diagnostic accuracy was 74.2% sensitivity and 64.9% specificity. The area under the ROC curve was 0.731. The results of this study show that quantification of the MET-TAC for each brain tumor identified by a dynamic MET-PET study could be helpful in the non-invasive discrimination of brain tumor subtypes, in particular gliomas.

Effects of metabolic syndrome on arterial function in different age groups: the Advanced Approach to Arterial Stiffness study.

PubMed

Topouchian, Jirar; Labat, Carlos; Gautier, Sylvie; Bäck, Magnus; Achimastos, Apostolos; Blacher, Jacques; Cwynar, Marcin; de la Sierra, Alejandro; Pall, Denes; Fantin, Francesco; Farkas, Katalin; Garcia-Ortiz, Luis; Hakobyan, Zoya; Jankowski, Piotr; Jelakovic, Ana; Kobalava, Zhanna; Konradi, Alexandra; Kotovskaya, Yulia; Kotsani, Marina; Lazareva, Irina; Litvin, Alexander; Milyagin, Viktor; Mintale, Iveta; Persson, Oscar; Ramos, Rafael; Rogoza, Anatoly; Ryliskyte, Ligita; Scuteri, Angelo; Sirenko, Yuriy; Soulis, Georges; Tasic, Nebojsa; Udovychenko, Maryna; Urazalina, Saule; Wohlfahrt, Peter; Zelveian, Parounak; Benetos, Athanase; Asmar, Roland

2018-04-01

The aim of the Advanced Approach to Arterial Stiffness study was to compare arterial stiffness measured simultaneously with two different methods in different age groups of middle-aged and older adults with or without metabolic syndrome (MetS). The specific effects of the different MetS components on arterial stiffness were also studied. This prospective, multicentre, international study included 2224 patients aged 40 years and older, 1664 with and 560 without MetS. Patients were enrolled in 32 centres from 18 European countries affiliated to the International Society of Vascular Health & Aging. Arterial stiffness was evaluated using the cardio-ankle vascular index (CAVI) and the carotid-femoral pulse wave velocity (CF-PWV) in four prespecified age groups: 40-49, 50-59, 60-74, 75-90 years. In this report, we present the baseline data of this study. Both CF-PWV and CAVI increased with age, with a higher correlation coefficient for CAVI (comparison of coefficients P < 0.001). Age-adjusted and sex-adjusted values of CF-PWV and CAVI were weakly intercorrelated (r = 0.06, P < 0.001). Age-adjusted and sex-adjusted values for CF-PWV but not CAVI were higher in presence of MetS (CF-PWV: 9.57 ± 0.06 vs. 8.65 ± 0.10, P < 0.001; CAVI: 8.34 ± 0.03 vs. 8.29 ± 0.04, P = 0.40; mean ± SEM; MetS vs. no MetS). The absence of an overall effect of MetS on CAVI was related to the heterogeneous effects of the components of MetS on this parameter: CAVI was positively associated with the high glycaemia and high blood pressure components, whereas lacked significant associations with the HDL and triglycerides components while exhibiting a negative association with the overweight component. In contrast, all five MetS components showed positive associations with CF-PWV. This large European multicentre study reveals a differential impact of MetS and age on CAVI and CF-PWV and suggests that age may have a more pronounced effect on CAVI, whereas MetS increases CF-PWV but not CAVI. This important finding may be due to heterogeneous effects of MetS components on CAVI. The clinical significance of these original results will be assessed during the longitudinal phase of the study.

The oleocanthal-based homovanillyl sinapate as a novel c-Met inhibitor

PubMed Central

Mohyeldin, Mohamed M.; Akl, Mohamed R.; Ebrahim, Hassan Y.; Dragoi, Ana Maria; Dykes, Samantha; Cardelli, James A.; El Sayed, Khalid A.

2016-01-01

The hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-Met) signaling axis has gained considerable attention as an attractive molecular target for therapeutic blockade of cancer. Inspired by the chemical structure of S (−)-oleocanthal, a natural secoiridoid from extra-virgin olive oil with documented anticancer activity against c-Met-dependent malignancies, the research presented herein reports on the discovery of the novel olive-derived homovanillyl sinapate (HVS) as a promising c-Met inhibitor. HVS was distinguished for its remarkable potency against wild-type c-Met and its oncogenic variant in cell-free assays and confirmed by in silico docking studies. Furthermore, HVS substantially impaired the c-Met-mediated growth across a broad spectrum of breast cancer cells, while similar treatment doses had no effect on the non-tumorigenic mammary epithelial cell growth. In addition, HVS caused a dose-dependent inhibition of HGF-induced, but not epidermal growth factor (EGF)-induced, cell scattering in addition to HGF-mediated migration, invasion, and 3-dimensional (3D) proliferation of tumor cell spheroids. HVS treatment effects were mediated via inhibition of ligand-mediated c-Met activation and its downstream mitogenic signaling and blocking molecular mediators involved in cellular motility across different cellular contexts. An interesting feature of HVS is its good selectivity for c-Met and Abelson murine leukemia viral oncogene homolog 1 (ABL1) when profiled against a panel of kinases. Docking studies revealed interactions likely to impart high dual affinity for both ABL1 and c-Met kinases. HVS markedly reduced tumor growth, showed excellent pharmacodynamics, and suppressed cell proliferation and microvessel density in an orthotopic model of triple negative breast cancer. Collectively, the present findings suggested that the oleocanthal-based HVS is a promising c-Met inhibitor lead entity with excellent therapeutic potential to control malignancies with aberrant c-Met activity. PMID:27086914

Effects of circulating member B of the family with sequence similarity 3 on the risk of developing metabolic syndrome and its components: A 5-year prospective study.

PubMed

Wang, Haoyu; Yu, Fadong; Zhang, Zhuo; Hou, Yuanyuan; Teng, Weiping; Shan, Zhongyan; Lai, Yaxin

2017-11-27

Member B of the family with sequence similarity 3 (FAM3B), also known as pancreatic-derived factor, is mainly synthesized and secreted by islet β-cells, and plays a role in abnormal metabolism of glucose and lipids. However, the prospective association of FAM3B with metabolic disorders remains unclear. The present study aimed to reveal the predictive relationship between pancreas-specific cytokine and metabolic syndrome (MetS). A total of 210 adults (88 men and 122 women) without MetS, aged between 40 and 65 years, were recruited and received a comprehensive health examination. Baseline serum FAM3B levels were determined by sandwich enzyme-linked immunosorbent assay. Subsequently, all participants underwent a follow-up examination after 5 years. MetS was identified in accordance with the International Diabetes Federation criteria. During follow up, 35.7% participants developed MetS. In comparison with the non-MetS group, participants with MetS had an increased serum FAM3B at baseline (21.85 ng/mL [19.38, 24.17 ng/mL] vs 28.56 ng/mL [25.32, 38.10 ng/mL], P < 0.001). Moreover, serum FAM3B was significantly associated with variations in fasting plasma insulin (r = -0.306, P < 0.001), homeostasis model assessment of β-cell function (r = -0.328, P < 0.001) and homeostasis model assessment of insulin resistance (r = -0.191, P = 0.006). Furthermore, a positive correlation between baseline FAM3B and the incidence of MetS was observed, even after multivariable adjustment (relative risk 1.23 [1.15, 1.31], P < 0.001). Furthermore, the optimal cut-off values of FAM3B was 23.98 ng/mL for predicting MetS based on the Youden Index. Elevated circulating FAM3B might be considered as a predictor of newly-onset MetS and its progression. © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Physical activity and cancer risk: dose-response and cancer, all sites and site-specific.

PubMed

Thune, I; Furberg, A S

2001-06-01

The association between physical activity and overall and site-specific cancer risk is elaborated in relation to whether any observed dose-response association between physical activity and cancer can be interpreted in terms of how much physical activity (type, intensity, duration, frequency) is needed to influence site- and gender-specific cancer risk. Observational studies were reviewed that have examined the independent effect of the volume of occupational physical activity (OPA) and/or leisure time physical activity (LPA) on overall and site-specific cancer risk. The evidence of cohort and case-control studies suggests that both leisure time and occupational physical activity protect against overall cancer risk, with a graded dose-response association suggested in both sexes. Confounding effects such as diet, body weight, and parity are often included as a covariate in the analyses, with little influence on the observed associations. A crude graded inverse dose-response association was observed between physical activity and colon cancer in 48 studies including 40,674 colon/colorectal cancer cases for both sexes. A dose-response effect of physical activity on colon cancer risk was especially observed, when participation in activities of at least moderate activity (>4.5 MET) and demonstrated by activities expressed as MET-hours per week. An observed inverse association with a dose-response relationship between physical activity and breast cancer was also identified in the majority of the 41 studies including 108,031 breast cancer cases. The dose-response relationship was in particular observed in case-control studies and supported by observations in cohort studies when participation in activities of at least moderate activity (>4.5 MET) and demonstrated by activities expressed by MET-hours per week. This association between physical activity and breast cancer risk is possibly dependent on age at exposure, age at diagnosis, menopausal status and other effect modifiers, e.g., body mass index. Furthermore, data concerning carcinoma of other cancers (prostate, lung, endometrium, ovary, and testicular cancers) are required. A protective effect of physical activity on site-specific cancer risk with a dose-response association between physical activity and colon and pre- and postmenopausal breast cancer supported by identified biological mechanisms has been observed. The optimal permutation of type, intensity, duration, and frequency of physical activity across the lifespan is unclear, but it is gender, age, and site specific and supports moderate activity (>4.5 MET) more than light activities (<4.5 MET). The complicated nature of the physical activity variable, combined with lack of knowledge regarding possible biological mechanisms operating between physical activity and cancer, warrants further studies including controlled clinical randomized trials.

Preliminary evidence of cognitive and brain abnormalities in uncomplicated adolescent obesity.

PubMed

Yau, Po Lai; Kang, Esther H; Javier, David C; Convit, Antonio

2014-08-01

To ascertain whether pediatric obesity without clinically significant insulin resistance (IR) impacts brain structure and function. Thirty obese and 30 matched lean adolescents, all without clinically significant IR or a diagnosis of metabolic syndrome (MetS), received comprehensive endocrine, neuropsychological, and MRI evaluations. Relative to lean adolescents, obese non-IR adolescents had significantly lower academic achievement (i.e., arithmetic and spelling) and tended to score lower on working memory, attention, psychomotor efficiency, and mental flexibility. In line with our prior work on adolescent MetS, memory was unaffected in uncomplicated obesity. Reductions in the thickness of the orbitofrontal and anterior cingulate cortices as well as reductions of microstructural integrity in major white matter tracts without gross volume changes were also uncovered. It was documented, for the first time, that adolescents with uncomplicated obesity already have subtle brain alterations and lower performance in selective cognitive domains. When interpreting these preliminary data in the context of our prior reports of similar, but more extensive brain findings in obese adolescents with MetS and T2DM, it was concluded that "uncomplicated" obesity may also result in subtle brain alterations, suggesting a possible dose effect with more severe metabolic dysregulation giving rise to greater abnormalities. Copyright © 2014 The Obesity Society.

Symbiosis of executive and selective attention in working memory

PubMed Central

Vandierendonck, André

2014-01-01

The notion of working memory (WM) was introduced to account for the usage of short-term memory resources by other cognitive tasks such as reasoning, mental arithmetic, language comprehension, and many others. This collaboration between memory and other cognitive tasks can only be achieved by a dedicated WM system that controls task coordination. To that end, WM models include executive control. Nevertheless, other attention control systems may be involved in coordination of memory and cognitive tasks calling on memory resources. The present paper briefly reviews the evidence concerning the role of selective attention in WM activities. A model is proposed in which selective attention control is directly linked to the executive control part of the WM system. The model assumes that apart from storage of declarative information, the system also includes an executive WM module that represents the current task set. Control processes are automatically triggered when particular conditions in these modules are met. As each task set represents the parameter settings and the actions needed to achieve the task goal, it will depend on the specific settings and actions whether selective attention control will have to be shared among the active tasks. Only when such sharing is required, task performance will be affected by the capacity limits of the control system involved. PMID:25152723

Symbiosis of executive and selective attention in working memory.

PubMed

Vandierendonck, André

2014-01-01

The notion of working memory (WM) was introduced to account for the usage of short-term memory resources by other cognitive tasks such as reasoning, mental arithmetic, language comprehension, and many others. This collaboration between memory and other cognitive tasks can only be achieved by a dedicated WM system that controls task coordination. To that end, WM models include executive control. Nevertheless, other attention control systems may be involved in coordination of memory and cognitive tasks calling on memory resources. The present paper briefly reviews the evidence concerning the role of selective attention in WM activities. A model is proposed in which selective attention control is directly linked to the executive control part of the WM system. The model assumes that apart from storage of declarative information, the system also includes an executive WM module that represents the current task set. Control processes are automatically triggered when particular conditions in these modules are met. As each task set represents the parameter settings and the actions needed to achieve the task goal, it will depend on the specific settings and actions whether selective attention control will have to be shared among the active tasks. Only when such sharing is required, task performance will be affected by the capacity limits of the control system involved.

Comparative Analysis of Metabolic Syndrome Components in over 15,000 African Americans Identifies Pleiotropic Variants: Results from the PAGE Study

PubMed Central

Carty, Cara L.; Bhattacharjee, Samsiddhi; Haessler, Jeff; Cheng, Iona; Hindorff, Lucia A.; Aroda, Vanita; Carlson, Christopher S.; Hsu, Chun-Nan; Wilkens, Lynne; Liu, Simin; Selvin, Elizabeth; Jackson, Rebecca; North, Kari E.; Peters, Ulrike; Pankow, James S.; Chatterjee, Nilanjan; Kooperberg, Charles

2014-01-01

Background Metabolic syndrome (MetS) refers to the clustering of cardio-metabolic risk factors including dyslipidemia, central adiposity, hypertension and hyperglycemia in individuals. Identification of pleiotropic genetic factors associated with MetS traits may shed light on key pathways or mediators underlying MetS. Methods and Results Using the Metabochip array in 15,148 African Americans (AA) from the PAGE Study, we identify susceptibility loci and investigate pleiotropy among genetic variants using a subset-based meta-analysis method, ASsociation-analysis-based-on-subSETs (ASSET). Unlike conventional models which lack power when associations for MetS components are null or have opposite effects, ASSET uses one-sided tests to detect positive and negative associations for components separately and combines tests accounting for correlations among components. With ASSET, we identify 27 SNPs in 1 glucose and 4 lipids loci (TCF7L2, LPL, APOA5, CETP, LPL, APOC1/APOE/TOMM40) significantly associated with MetS components overall, all P< 2.5e-7, the Bonferroni adjusted P-value. Three loci replicate in a Hispanic population, n=5172. A novel AA-specific variant, rs12721054/APOC1, and rs10096633/LPL are associated with ≥3 MetS components. We find additional evidence of pleiotropy for APOE, TOMM40, TCF7L2 and CETP variants, many with opposing effects; e.g. the same rs7901695/TCF7L2 allele is associated with increased odds of high glucose and decreased odds of central adiposity. Conclusions We highlight a method to increase power in large-scale genomic association analyses, and report a novel variant associated with all MetS components in AA. We also identify pleiotropic associations that may be clinically useful in patient risk profiling and for informing translational research of potential gene targets and medications. PMID:25023634

Analysis of metabolic syndrome components in >15 000 african americans identifies pleiotropic variants: results from the population architecture using genomics and epidemiology study.

PubMed

Carty, Cara L; Bhattacharjee, Samsiddhi; Haessler, Jeff; Cheng, Iona; Hindorff, Lucia A; Aroda, Vanita; Carlson, Christopher S; Hsu, Chun-Nan; Wilkens, Lynne; Liu, Simin; Selvin, Elizabeth; Jackson, Rebecca; North, Kari E; Peters, Ulrike; Pankow, James S; Chatterjee, Nilanjan; Kooperberg, Charles

2014-08-01

Metabolic syndrome (MetS) refers to the clustering of cardiometabolic risk factors, including dyslipidemia, central adiposity, hypertension, and hyperglycemia, in individuals. Identification of pleiotropic genetic factors associated with MetS traits may shed light on key pathways or mediators underlying MetS. Using the Metabochip array in 15 148 African Americans from the Population Architecture using Genomics and Epidemiology (PAGE) study, we identify susceptibility loci and investigate pleiotropy among genetic variants using a subset-based meta-analysis method, ASsociation-analysis-based-on-subSETs (ASSET). Unlike conventional models that lack power when associations for MetS components are null or have opposite effects, Association-analysis-based-on-subsets uses 1-sided tests to detect positive and negative associations for components separately and combines tests accounting for correlations among components. With Association-analysis-based-on-subsets, we identify 27 single nucleotide polymorphisms in 1 glucose and 4 lipids loci (TCF7L2, LPL, APOA5, CETP, and APOC1/APOE/TOMM40) significantly associated with MetS components overall, all P<2.5e-7, the Bonferroni adjusted P value. Three loci replicate in a Hispanic population, n=5172. A novel African American-specific variant, rs12721054/APOC1, and rs10096633/LPL are associated with ≥3 MetS components. We find additional evidence of pleiotropy for APOE, TOMM40, TCF7L2, and CETP variants, many with opposing effects (eg, the same rs7901695/TCF7L2 allele is associated with increased odds of high glucose and decreased odds of central adiposity). We highlight a method to increase power in large-scale genomic association analyses and report a novel variant associated with all MetS components in African Americans. We also identify pleiotropic associations that may be clinically useful in patient risk profiling and for informing translational research of potential gene targets and medications. © 2014 American Heart Association, Inc.

Fatness mediates the influence of muscular fitness on metabolic syndrome in Colombian collegiate students.

PubMed

García-Hermoso, Antonio; Carrillo, Hugo Alejandro; González-Ruíz, Katherine; Vivas, Andrés; Triana-Reina, Héctor Reynaldo; Martínez-Torres, Javier; Prieto-Benavidez, Daniel Humberto; Correa-Bautista, Jorge Enrique; Ramos-Sepúlveda, Jeison Alexander; Villa-González, Emilio; Peterson, Mark D; Ramírez-Vélez, Robinson

2017-01-01

The purpose of this study was two-fold: to analyze the association between muscular fitness (MF) and clustering of metabolic syndrome (MetS) components, and to determine if fatness parameters mediate the association between MF and MetS clustering in Colombian collegiate students. This cross-sectional study included a total of 886 (51.9% women) healthy collegiate students (21.4 ± 3.3 years old). Standing broad jump and isometric handgrip dynamometry were used as indicators of lower and upper body MF, respectively. Also, a MF score was computed by summing the standardized values of both tests, and used to classify adults as fit or unfit. We also assessed fat mass, body mass index, waist-to-height ratio, and abdominal visceral fat, and categorized individuals as low and high fat using international cut-offs. A MetS cluster score was derived by calculating the sum of the sample-specific z-scores from the triglycerides, HDL cholesterol, fasting glucose, waist circumference, and arterial blood pressure. Linear regression models were used to examine whether the association between MF and MetS cluster was mediated by the fatness parameters. Data were collected from 2013 to 2016 and the analysis was done in 2016. Findings revealed that the best profiles (fit + low fat) were associated with lower levels of the MetS clustering (p <0.001 in the four fatness parameters), compared with unfit and fat (unfit + high fat) counterparts. Linear regression models indicated a partial mediating effect for fatness parameters in the association of MF with MetS clustering. Our findings indicate that efforts to improve MF in young adults may decrease MetS risk partially through an indirect effect on improvements to adiposity levels. Thus, weight reduction should be taken into account as a complementary goal to improvements in MF within exercise programs.

Fatness mediates the influence of muscular fitness on metabolic syndrome in Colombian collegiate students

PubMed Central

Carrillo, Hugo Alejandro; González-Ruíz, Katherine; Vivas, Andrés; Triana-Reina, Héctor Reynaldo; Martínez-Torres, Javier; Prieto-Benavidez, Daniel Humberto; Ramos-Sepúlveda, Jeison Alexander; Villa-González, Emilio

2017-01-01

The purpose of this study was two-fold: to analyze the association between muscular fitness (MF) and clustering of metabolic syndrome (MetS) components, and to determine if fatness parameters mediate the association between MF and MetS clustering in Colombian collegiate students. This cross-sectional study included a total of 886 (51.9% women) healthy collegiate students (21.4 ± 3.3 years old). Standing broad jump and isometric handgrip dynamometry were used as indicators of lower and upper body MF, respectively. Also, a MF score was computed by summing the standardized values of both tests, and used to classify adults as fit or unfit. We also assessed fat mass, body mass index, waist-to-height ratio, and abdominal visceral fat, and categorized individuals as low and high fat using international cut-offs. A MetS cluster score was derived by calculating the sum of the sample-specific z-scores from the triglycerides, HDL cholesterol, fasting glucose, waist circumference, and arterial blood pressure. Linear regression models were used to examine whether the association between MF and MetS cluster was mediated by the fatness parameters. Data were collected from 2013 to 2016 and the analysis was done in 2016. Findings revealed that the best profiles (fit + low fat) were associated with lower levels of the MetS clustering (p <0.001 in the four fatness parameters), compared with unfit and fat (unfit + high fat) counterparts. Linear regression models indicated a partial mediating effect for fatness parameters in the association of MF with MetS clustering. Our findings indicate that efforts to improve MF in young adults may decrease MetS risk partially through an indirect effect on improvements to adiposity levels. Thus, weight reduction should be taken into account as a complementary goal to improvements in MF within exercise programs. PMID:28296952

In vivo and in silico dynamics of the development of Metabolic Syndrome.

PubMed

Rozendaal, Yvonne J W; Wang, Yanan; Paalvast, Yared; Tambyrajah, Lauren L; Li, Zhuang; Willems van Dijk, Ko; Rensen, Patrick C N; Kuivenhoven, Jan A; Groen, Albert K; Hilbers, Peter A J; van Riel, Natal A W

2018-06-01

The Metabolic Syndrome (MetS) is a complex, multifactorial disorder that develops slowly over time presenting itself with large differences among MetS patients. We applied a systems biology approach to describe and predict the onset and progressive development of MetS, in a study that combined in vivo and in silico models. A new data-driven, physiological model (MINGLeD: Model INtegrating Glucose and Lipid Dynamics) was developed, describing glucose, lipid and cholesterol metabolism. Since classic kinetic models cannot describe slowly progressing disorders, a simulation method (ADAPT) was used to describe longitudinal dynamics and to predict metabolic concentrations and fluxes. This approach yielded a novel model that can describe long-term MetS development and progression. This model was integrated with longitudinal in vivo data that was obtained from male APOE*3-Leiden.CETP mice fed a high-fat, high-cholesterol diet for three months and that developed MetS as reflected by classical symptoms including obesity and glucose intolerance. Two distinct subgroups were identified: those who developed dyslipidemia, and those who did not. The combination of MINGLeD with ADAPT could correctly predict both phenotypes, without making any prior assumptions about changes in kinetic rates or metabolic regulation. Modeling and flux trajectory analysis revealed that differences in liver fluxes and dietary cholesterol absorption could explain this occurrence of the two different phenotypes. In individual mice with dyslipidemia dietary cholesterol absorption and hepatic turnover of metabolites, including lipid fluxes, were higher compared to those without dyslipidemia. Predicted differences were also observed in gene expression data, and consistent with the emergence of insulin resistance and hepatic steatosis, two well-known MetS co-morbidities. Whereas MINGLeD specifically models the metabolic derangements underlying MetS, the simulation method ADAPT is generic and can be applied to other diseases where dynamic modeling and longitudinal data are available.

Sex- and age-specific associations between major depressive disorder and metabolic syndrome in two general population samples in Germany.

PubMed

Block, Andrea; Schipf, Sabine; Van der Auwera, Sandra; Hannemann, Anke; Nauck, Matthias; John, Ulrich; Völzke, Henry; Freyberger, Harald Jürgen; Dörr, Marcus; Felix, Stephan; Zygmunt, Marek; Wallaschofski, Henri; Grabe, Hans Jörgen

2016-11-01

Major depressive disorder (MDD) has been associated with the Metabolic Syndrome (MetS). As previous data strongly suggested sex and age effects on this association, this study aimed to analyse the association between MDD and MetS in two general population samples under explicit consideration of sex and age. This study analysed cross-sectional data based on two independent general population samples: SHIP-0 (n = 4083; 20-81 years; 49.4% male) and SHIP-TREND-0 (n = 3957; 20-83 years; 49.0% male) that were part of the Study of Health in Pomerania. MDD (SHIP-0: 12.6%; SHIP-TREND-0: 27.2%) was assessed using the Composite International Diagnostic-Screener (CID-S) in both samples. Interview assessment of MDD diagnosis according to Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria was performed in SHIP-TREND-0 (18.1% MDD). MetS was defined by abdominal obesity, elevated blood pressure, elevated glucose, elevated triglycerides and reduced high-density lipoprotein cholesterol according to established criteria. Data analysis was performed sex- and age-stratified. Prevalence of MetS was high in both samples: 19.4% of females and 30.2% of males in SHIP-0 and 22.1% and 33.2% in SHIP-TREND-0, respectively. Effect modifications were observed by sex and age on the association between MDD and MetS. Particularly, younger females (20-49 years) with MDD were more often affected by MetS than younger females without MDD: OR = 2.21 (95% CI = 1.39-3.50). This association vanished in elderly participants (50-82 years). The data suggest that especially younger (presumably pre-menopausal) females with MDD are more likely to have MetS than those without major depressive disorders, and that age extenuates this association.

How youth-friendly are pharmacies in New Zealand? Surveying aspects of accessibility and the pharmacy environment using a youth participatory approach.

PubMed

Horsfield, Emma; Kelly, Fiona; Clark, Terryann; Sheridan, Janie

2014-01-01

The international youth population has significant unmet health needs, and there have been many calls to increase youth health care access. Community pharmacies may be able to help address these needs, but very little research has investigated this area and it is not known whether the current community pharmacy setting is acceptable or appropriate for youth. 1) To obtain information on physical factors which could affect young people's use of community pharmacies in New Zealand, including accessibility, opening times and the physical youth-friendliness of the pharmacy environment. 2) To involve and utilize young people in the research process, in order to understand their needs and interpretation of survey data. This study applied a cross sectional survey design, informed by a sequential youth participatory approach. A questionnaire was developed in consultation with a youth advisory group (YAG). Questionnaires distributed to pharmacists at 500 randomly selected pharmacies nationwide between May and September 2011 collected information on whether the pharmacy met selected youth-friendly criteria. These included physical aspects of youth-friendliness, such as opening times and the pharmacy environment. The YAG also provided a youth perspective in the interpretation of the results. Three mail shots achieved a response rate of 50.5%. Most respondents reported the pharmacy to be accessible by public transport and many had extended opening hours. Although most pharmacies met some youth-friendly criteria with regards to the pharmacy environment (e.g. having a private consultation area), more specific criteria (such as displaying youth health information) were usually not met. Interpretive feedback from the YAG highlighted areas for improvement. Pharmacies show potential as youth-friendly health care access points and most already meet some youth-friendly criteria. Areas identified for improvement will require a greater youth focus from the profession, and should be undertaken in consultation with young people. We recommend the use of youth participation approaches in future pharmacy practice research into youth health services. Copyright © 2014 Elsevier Inc. All rights reserved.

Association of circulating total bilirubin with the metabolic syndrome and type 2 diabetes: A systematic review and meta-analysis of observational evidence.

PubMed

Nano, J; Muka, T; Cepeda, M; Voortman, T; Dhana, K; Brahimaj, A; Dehghan, A; Franco, O H

2016-12-01

Emerging evidence suggests that bilirubin levels might be associated with the metabolic syndrome (MetS) and type 2 diabetes (T2D), although the nature of the association remains unclear. This systematic review and meta-analysis investigated the relationship between total plasma bilirubin and the risk of MetS and T2D. Relevant studies were identified using five databases (Embase, Medline [Ovid], Web of Science, PubMed, Cochrane Central and Google Scholar), with the last search done on 21 October 2015. Study references were checked and authors contacted to identify additional studies. Randomized controlled trials, and cohort, case-control and cross-sectional studies of adults examining the association between blood bilirubin levels and MetS and T2D were included, irrespective of language and date of publication. Abstract and full-text selection was done by two independent reviewers, with a third reviewer available in case of disagreement. Data were extracted by two independent reviewers using a predesigned data collection form. MetS and T2D. Summary estimates were obtained by random-effects meta-analysis. Of the 2313 searched references, 16 observational studies (11 cross-sectional, two prospective, one that was both cross-sectional and prospective, two retrospective and one national survey) met our inclusion criteria. Overall, data were available for 175,911 non-overlapping participants, including 7414 MetS cases and 9406 T2D cases. In the meta-analysis of seven cross-sectional studies, the pooled odds ratio (95% confidence interval) for MetS in a comparison of extreme tertiles of serum bilirubin levels was 0.70 (95% CI: 0.62, 0.78), whereas no significant association was found for the pooled estimated relative risk between two prospective studies (0.57, 95% CI: 0.11, 2.94). The corresponding estimate was 0.77 (95% CI: 0.67, 0.87) for T2D from four cross-sectional studies. The available evidence, mainly from cross-sectional studies, supports an inverse association of bilirubin levels with adverse metabolic outcomes. Large-scale prospective studies are now needed to establish whether bilirubin levels may be useful in the prevention of MetS and T2D. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

How the integration of traditional birth attendants with formal health systems can increase skilled birth attendance.

PubMed

Byrne, Abbey; Morgan, Alison

2011-11-01

Forty years of safe motherhood programming has demonstrated that isolated interventions will not reduce maternal mortality sufficiently to achieve MDG 5. Although skilled birth attendants (SBAs) can intervene to save lives, traditional birth attendants (TBAs) are often preferred by communities. Considering the value of both TBAs and SBAs, it is important to review strategies for maximizing their respective strengths. To describe mechanisms to integrate TBAs with the health system to increase skilled birth attendance and examine the components of successful integration. A systematic review of interventions linking TBAs and formal health workers, measuring outcomes of skilled birth attendance, referrals, and facility deliveries. Thirty-three articles met the selection criteria. Mechanisms used for integration included training and supervision of TBAs, collaboration skills for health workers, inclusion of TBAs at health facilities, communication systems, and clear definition of roles. Impact on skilled birth attendance depended on selection of TBAs, community participation, and addressing barriers to access. Successful approaches were context-specific. The integration of TBAs with formal health systems increases skilled birth attendance. The greatest impact is seen when TBA integration is combined with complementary actions to overcome context-specific barriers to contact among SBAs, TBAs, and women. Copyright © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Adapted Finnegan scoring list for observation of anti-depressant exposed infants.

PubMed

Kieviet, Noera; van Ravenhorst, Mariëtte; Dolman, Koert M; van de Ven, Peter M; Heres, Marion; Wennink, Hanneke; Honig, Adriaan

2015-01-01

The Finnegan scoring list (FSL) is widely used to screen for poor neonatal adaptation in infants exposed to anti-depressants in utero. However, the large number of FSL-items and differential weighing of each item is time consuming. The aim of this study was to shorten and simplify the FSL yet preserving its clinimetric properties. This observational study examined infants exposed to an anti-depressant during pregnancy admitted for at least 72 h on a maternity ward. Trained nurses completed the FSL three times daily. Items for the adapted FSL were selected through forward analysis whereby the number of selected items was based on the area under the curve (AUC). Internal validity was assessed by cross-validation. 183 infants met the inclusion criteria. By forward analysis eight equally-weighed items resulted in an AUC of 0.91. In cross-validation, the mean AUC was 0.89 for 8 items. This adapted FSL had a sensitivity of 97.7% and specificity of 37.0% and a sensitivity of 41.9% and specificity of 86.2% regarding a cut-off of, respectively, 1 and 2. An adapted FSL with eight equally-weighed items has acceptable clinimetric properties and can serve as an easy to apply screening tool in infants exposed to anti-depressants during pregnancy.

Monitoring of water supply connections as an element to reduce apparent losses of water?

NASA Astrophysics Data System (ADS)

Gwoździej-Mazur, Joanna

2017-11-01

Measuring instruments are designed to measure a given physical value, to process the obtained information and forward it to the observer. They are designed to perform specific tasks in specific working conditions and meeting the envisaged requirements. The most important requirement to be met by measuring instruments, is to preserve the established metrological characteristics. The basic and most common instrument for measuring the volume of flowing water is the water meter. Selecting the right water meter in the operating conditions is not an easy issue. The problem has been further intensified by decrease of water consumption which began in the 90s of the twentieth century and continuing to the present day. As a result, there has changed the structure of water consumption in both the residential and industrial applications. In this situation, a right selection of the optimal water meter it is an important case. The article presents the results of research in the field of characteristic flows in the water supply connections in multi-family housing using modern monitoring systems. It has been presented the calculated inequality ratio of water consumption, which can be helpful when designing a plumbing systems. In addition, the structure of water consumption due to the typical flow ranges was determined.

Fear of negative evaluation biases social evaluation inference: evidence from a probabilistic learning task.

PubMed

Button, Katherine S; Kounali, Daphne; Stapinski, Lexine; Rapee, Ronald M; Lewis, Glyn; Munafò, Marcus R

2015-01-01

Fear of negative evaluation (FNE) defines social anxiety yet the process of inferring social evaluation, and its potential role in maintaining social anxiety, is poorly understood. We developed an instrumental learning task to model social evaluation learning, predicting that FNE would specifically bias learning about the self but not others. During six test blocks (3 self-referential, 3 other-referential), participants (n = 100) met six personas and selected a word from a positive/negative pair to finish their social evaluation sentences "I think [you are / George is]…". Feedback contingencies corresponded to 3 rules, liked, neutral and disliked, with P[positive word correct] = 0.8, 0.5 and 0.2, respectively. As FNE increased participants selected fewer positive words (β = -0.4, 95% CI -0.7, -0.2, p = 0.001), which was strongest in the self-referential condition (FNE × condition 0.28, 95% CI 0.01, 0.54, p = 0.04), and the neutral and dislike rules (FNE × condition × rule, p = 0.07). At low FNE the proportion of positive words selected for self-neutral and self-disliked greatly exceeded the feedback contingency, indicating poor learning, which improved as FNE increased. FNE is associated with differences in processing social-evaluative information specifically about the self. At low FNE this manifests as insensitivity to learning negative self-referential evaluation. High FNE individuals are equally sensitive to learning positive or negative evaluation, which although objectively more accurate, may have detrimental effects on mental health.

Medical Exercise Therapy for Treating Musculoskeletal Pain: A Narrative Review of Results from Randomized Controlled Trials with a Theoretical Perspective.

PubMed

Lorås, H; Østerås, B; Torstensen, T A; Østerås, H

2015-09-01

The purpose of this narrative review is to present an overview and theoretical rationale of medical exercise therapy (MET) as a physiotherapeutic rehabilitation treatment for musculoskeletal pain conditions. Results from randomized controlled trials (RCTs) conducted on MET are also presented. Computerized searches for any RCTs were conducted on the MET concept in the databases PubMed, Medline, Embase and ISI Web of science up to 2013. Overall findings from five included MET RCTs are long-term (≥1 year) reductions in pain and improved physical and functional capabilities. These results are interpreted in the context of the biopsychosocial model, advancing the view of a dynamic interaction among physiologic, psychological and social factors that influence pain modulation. MET is a biopsychosocial treatment that reduces pain and improves activities of daily living in patients with a musculoskeletal pain condition. Pain modulation is a key feature of MET, and an important area for further research is to elucidate the specific mechanisms behind the treatment effects. Copyright © 2015 John Wiley & Sons, Ltd.

The role of bariatric surgery in the management of nonalcoholic fatty liver disease and metabolic syndrome.

PubMed

Aguilar-Olivos, Nancy E; Almeda-Valdes, Paloma; Aguilar-Salinas, Carlos A; Uribe, Misael; Méndez-Sánchez, Nahum

2016-08-01

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. NAFLD is strongly associated with obesity and metabolic syndrome (MetS). Current treatment of NAFLD is based on weight reduction. Bariatric surgery is the most effective treatment for morbid obesity and its associated metabolic comorbidities. There is evidence indicating that bariatric surgery improves histological and biochemical parameters of NAFLD, but currently is not considered a treatment option for NAFLD. The aim of this work is to review the evidence for the effects of bariatric surgery on NAFLD and the MetS. We found that insulin resistance, alterations in glucose metabolism, hypertension, plasma lipids, transaminases, liver steatosis, steatohepatitis and fibrosis improve after bariatric surgery. Weight loss and improvement of NAFLD are greater after RYGB than after other interventions. These findings were obtained from retrospective or cohort studies. There are no studies designed to evaluate liver-specific mortality, liver transplantation, or quality of life. Patients with indications for bariatric surgery will benefit from the improvements in the MetS and NAFLD. Copyright © 2016 Elsevier Inc. All rights reserved.

Identification of new ligands for the methionine biosynthesis transcriptional regulator (MetJ) by FAC-MS.

PubMed

Martí-Arbona, Ricardo; Teshima, Munehiro; Anderson, Penelope S; Nowak-Lovato, Kristy L; Hong-Geller, Elizabeth; Unkefer, Clifford J; Unkefer, Pat J

2012-01-01

We have developed a high-throughput approach using frontal affinity chromatography coupled to mass spectrometry (FAC-MS) for the identification and characterization of the small molecules that modulate transcriptional regulator (TR) binding to TR targets. We tested this approach using the methionine biosynthesis regulator (MetJ). We used effector mixtures containing S-adenosyl-L-methionine (SAM) and S-adenosyl derivatives as potential ligands for MetJ binding. The differences in the elution time of different compounds allowed us to rank the binding affinity of each compound. Consistent with previous results, FAC-MS showed that SAM binds to MetJ with the highest affinity. In addition, adenine and 5'-deoxy-5'-(methylthio)adenosine bind to the effector binding site on MetJ. Our experiments with MetJ demonstrate that FAC-MS is capable of screening complex mixtures of molecules and identifying high-affinity binders to TRs. In addition, FAC-MS experiments can be used to discriminate between specific and nonspecific binding of the effectors as well as to estimate the dissociation constant (K(d)) for effector-TR binding. Copyright © 2012 S. Karger AG, Basel.

Community-based physical activity and nutrition programme for adults with metabolic syndrome in Vietnam: study protocol for a cluster-randomised controlled trial

PubMed Central

Tran, Van Dinh; Lee, Andy H; Jancey, Jonine; James, Anthony P; Howat, Peter; Thi Phuong Mai, Le

2016-01-01

Introduction Metabolic syndrome (MetS) is a cluster of risk factors for cardiovascular diseases and type II diabetes. In Vietnam, more than one-quarter of its population aged 50–65 have MetS. This cluster-randomised controlled trial aims to evaluate the effectiveness of interventions to increase levels of physical activity and improve dietary behaviours among Vietnamese adults aged 50–65 years with MetS. Method and analysis This 6-month community-based intervention includes a range of strategies to improve physical activity and nutrition for adults with MetS in Hanam, a province located in northern Vietnam. 600 participants will be recruited from 6 communes with 100 participants per commune. The 6 selected communes will be randomly allocated to either an intervention group (m=3; n=300) or a control group (m=3; n=300). The intervention comprises booklets, education sessions, resistance bands and attending local walking groups that provide information and encourage participants to improve their physical activity and healthy eating behaviours during the 6-month period. The control group participants will receive standard and 1-time advice. Social cognitive theory is the theoretical concept underpinning this study. Measurements will be taken at baseline and postintervention to evaluate programme effectiveness. Ethics and dissemination The research protocol was approved by the Curtin University Human Research Ethics Committee (approval number: HR139/2014). The results of the study will be disseminated through publications, reports and conference presentations. Trial registration number ACTRN12614000811606. PMID:27256094

Lower urinary tract symptoms are associated with low levels of serum serotonin, high levels of adiponectin and fasting glucose, and benign prostatic enlargement.

PubMed

Haghsheno, Mohammad-Ali; Mellström, Dan; Peeker, Ralph; Hammarsten, Jan; Lorentzon, Mattias; Sundh, Valter; Karlsson, Magnus; Ohlsson, Claes; Damber, Jan-Erik

2015-04-01

The aim of this study was to test whether lower urinary tract symptoms (LUTS) and urinary incontinence are associated with the metabolic syndrome (MetS). The association between LUTS and benign prostatic enlargement (BPE) was also investigated. A cross-sectional, representative risk factor analysis of LUTS, as measured by the International Prostate Symptom Score (IPSS), and urinary incontinence was conducted. Among 950 representative individuals, aged 69-81 years, the association between clinical, anthropometric, endocrine, metabolic and inflammatory factors on the one hand, as both major and minor aspects of MetS, and LUTS and urinary incontinence, on the other hand, was analysed. The prostate gland volume was measured in a subgroup of 155 randomly selected individuals and the association between LUTS and BPE was estimated. No significant association was found between LUTS or urinary incontinence and the major aspects of the MetS. However, in a multivariate analysis, serum serotonin showed an independent negative correlation with LUTS and with urinary incontinence while fasting serum glucose and serum adiponectin showed a positive correlation with LUTS. Furthermore, in a subgroup of 155 individuals, the prostate gland volume correlated positively with LUTS. The study did not show an association between LUTS or urinary incontinence and the major components of the MetS. However, serum serotonin showed an independent negative correlation with LUTS and with urinary incontinence while fasting serum glucose and serum adiponectin showed a positive correlation with LUTS. The data confirm the general knowledge that BPE may be one of the causative factors of LUTS.

Are school vending machines loaded with calories and fat: an assessment of 106 middle and high schools.

PubMed

Pasch, Keryn E; Lytle, Leslie A; Samuelson, Anne C; Farbakhsh, Kian; Kubik, Martha Y; Patnode, Carrie D

2011-04-01

The purpose of this study was to describe the extent to which vending offerings in 106 schools in the St. Paul-Minneapolis, Minnesota metropolitan area, met criteria for types of beverages, fat, and calories based on selected criteria offered by the Institute of Medicine. Schools where youth participants were attending for the 2006-2007 school year were identified and invited to participate in the study (n = 143); 81% of schools (n = 116) agreed to participate. Of the 116 schools, 106 had vending machines. Across schools with vending machines (n = 106), 5085 food and 8442 beverage items were offered. Overall, only 18% of beverage items met criteria for calories and type of beverage; significantly more items in public schools met the criteria as compared to private schools (19% vs 12%; p < .01). This difference was also significant for high schools as compared to middle schools (18% vs 22%; p < .01). For food items, 41% met calorie criteria, 45% met fat criteria, and 22% met both fat and calorie criteria. Significantly more food items met both criteria in public than private schools (22% vs 18%; p = .01), while high schools (22%) and middle schools (21%) were similar. A very small proportion of foods (< 5%) would have met the full criteria suggested by the Institute of Medicine for competitive foods. Overall, foods and beverages offered in vending machines continue to be high in fat and calories. Public schools are doing a slightly better job of providing healthy foods as compared to private schools. © 2011, American School Health Association.

Are School Vending Machines Loaded with Calories and Fat: An Assessment of 106 Middle and High Schools

PubMed Central

PASCH, KERYN E.; LYTLE, LESLIE A.; SAMUELSON, ANNE C.; FARBAKHSH, KIAN; KUBIK, MARTHA Y.; PATNODE, CARRIE D.

2013-01-01

Background The purpose of this study was to describe the extent to which vending offerings in 106 schools in the St. Paul-Minneapolis, Minnesota metropolitan area met criteria for types of beverages, fat and calories based on selected criteria offered by the Institute of Medicine. Methods Schools where youth participants were attending for the 2006-2007 school year were identified and invited to participate in the study (n=143); 81% of schools (n=116) agreed to participate. Results Of the 116 schools, 106 had vending machines. Across schools with vending machines (n=106), 5085 food and 8442 beverage items were offered. Overall, only 18% of beverage items met criteria for calories and type of beverage; significantly more items in public schools met the criteria as compared to private schools (19% vs. 12%; p<0.01). This difference was also significant for high schools as compared to middle schools (18% vs. 22%; p<0.01). For food items, 41% met calorie criteria, 45% met fat criteria, and 22% met both fat and calorie criteria. Significantly more food items met both criteria in public than private schools (22% vs. 18%; p=0.01), while high schools (22%) and middle schools (21%) were similar. A very small proportion of foods (<5%) would have met the full criteria suggested by the Institute of Medicine for competitive foods.. Conclusion Overall, foods and beverages offered in vending machines continue to be high in fat and calories. Public schools are doing a slightly better job of providing healthy foods as compared to private schools. PMID:21392013

Does S-Metolachlor Affect the Performance of Pseudomonas sp. Strain ADP as Bioaugmentation Bacterium for Atrazine-Contaminated Soils?

PubMed Central

Viegas, Cristina A.; Costa, Catarina; André, Sandra; Viana, Paula; Ribeiro, Rui; Moreira-Santos, Matilde

2012-01-01

Atrazine (ATZ) and S-metolachlor (S-MET) are two herbicides widely used, often as mixtures. The present work examined whether the presence of S-MET affects the ATZ-biodegradation activity of the bioaugmentation bacterium Pseudomonas sp. strain ADP in a crop soil. S-MET concentrations were selected for their relevance in worst-case scenarios of soil contamination by a commercial formulation containing both herbicides. At concentrations representative of application of high doses of the formulation (up to 50 µg g−1 of soil, corresponding to a dose approximately 50× higher than the recommended field dose (RD)), the presence of pure S-MET significantly affected neither bacteria survival (∼107 initial viable cells g−1 of soil) nor its ATZ-mineralization activity. Consistently, biodegradation experiments, in larger soil microcosms spiked with 20× or 50×RD of the double formulation and inoculated with the bacterium, revealed ATZ to be rapidly (in up to 5 days) and extensively (>96%) removed from the soil. During the 5 days, concentration of S-MET decreased moderately to about 60% of the initial, both in inoculated and non-inoculated microcosms. Concomitantly, an accumulation of the two metabolites S-MET ethanesulfonic acid and S-MET oxanilic acid was found. Despite the dissipation of almost all the ATZ from the treated soils, the respective eluates were still highly toxic to an aquatic microalgae species, being as toxic as those from the untreated soil. We suggest that this high toxicity may be due to the S-MET and/or its metabolites remaining in the soil. PMID:22615921

Do air cleaners make a difference in treating allergic disease in homes?

PubMed

Reisman, R E

2001-12-01

The purpose of this review is to objectively critique available data regarding the clinical benefits of room air cleaners and to provide physicians and patients with a reasonable recommendation of their utility in treatment of inhalant allergic disease. Data were obtained from published studies and reviews. The specific reviewed studies met the following criteria: 1) selection of patients with clinical allergic disease confirmed by detection of allergen-specific immunoglobulin E; 2) use of an effective air filter; 3) clinical and laboratory evaluation of results; and 4) measurement of the results of air filtration on environmental allergen or airborne particulate levels. The studies were conducted in a double-blind manner. Conclusions of two previous reviews are also incorporated in this paper. The results of the published studies and summary reviews show minimal, if any, effectiveness of room air cleaners in treatment of allergic respiratory disease. Room air cleaners should not be recommended for people with inhalant allergic disease.

Do childhood vaccines have non-specific effects on mortality?

PubMed Central

Cooper, William O.; Boyce, Thomas G.; Wright, Peter F.; Griffin, Marie R.

2003-01-01

A recent article by Kristensen et al. suggested that measles vaccine and bacille Calmette-Gu rin (BCG) vaccine might reduce mortality beyond what is expected simply from protection against measles and tuberculosis. Previous reviews of the potential effects of childhood vaccines on mortality have not considered methodological features of reviewed studies. Methodological considerations play an especially important role in observational assessments, in which selection factors for vaccination may be difficult to ascertain. We reviewed 782 English language articles on vaccines and childhood mortality and found only a few whose design met the criteria for methodological rigor. The data reviewed suggest that measles vaccine delivers its promised reduction in mortality, but there is insufficient evidence to suggest a mortality benefit above that caused by its effect on measles disease and its sequelae. Our review of the available data in the literature reinforces how difficult answering these considerations has been and how important study design will be in determining the effect of specific vaccines on all-cause mortality. PMID:14758409

Cooling towers, the neglected energy conservations and money making machine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Burger, R.

1996-12-31

The heat Rejection Industry defines a nominal cooling tower as circulating three gallons of water per minute (GPM) per ton of refrigeration from entering the tower at 95 {degrees}F, Hot Water temperature (HWT), Leaving at 85{degrees}F Cold Water Temperature (CWT) at a Design Wet Bulb of 70{degrees}F (WBT). Manufacturers then provide a selection chart based on various wet bulb temperatures and HWTs. The wet bulb fluctuates and varies throughout the world since it is the combination ambient temperature, relative humidity, and/or dew point. Different HWT and CWT requirements are usually charted as they change, so that the user can selectmore » the nominal cooling tower model recommended by the manufacturer. In the specification of cooling towers it is necessary to clearly understand the definition of nominal cooling tower, and to make sure the specification you need addressed can be met by the system you purchase. This should be tested prior to final acceptance.« less

Molecular Tools for Diagnosis of Visceral Leishmaniasis: Systematic Review and Meta-Analysis of Diagnostic Test Accuracy

PubMed Central

de Ruiter, C. M.; van der Veer, C.; Leeflang, M. M. G.; Deborggraeve, S.; Lucas, C.

2014-01-01

Molecular methods have been proposed as highly sensitive tools for the detection of Leishmania parasites in visceral leishmaniasis (VL) patients. Here, we evaluate the diagnostic accuracy of these tools in a meta-analysis of the published literature. The selection criteria were original studies that evaluate the sensitivities and specificities of molecular tests for diagnosis of VL, adequate classification of study participants, and the absolute numbers of true positives and negatives derivable from the data presented. Forty studies met the selection criteria, including PCR, real-time PCR, nucleic acid sequence-based amplification (NASBA), and loop-mediated isothermal amplification (LAMP). The sensitivities of the individual studies ranged from 29 to 100%, and the specificities ranged from 25 to 100%. The pooled sensitivity of PCR in whole blood was 93.1% (95% confidence interval [CI], 90.0 to 95.2), and the specificity was 95.6% (95% CI, 87.0 to 98.6). The specificity was significantly lower in consecutive studies, at 63.3% (95% CI, 53.9 to 71.8), due either to true-positive patients not being identified by parasitological methods or to the number of asymptomatic carriers in areas of endemicity. PCR for patients with HIV-VL coinfection showed high diagnostic accuracy in buffy coat and bone marrow, ranging from 93.1 to 96.9%. Molecular tools are highly sensitive assays for Leishmania detection and may contribute as an additional test in the algorithm, together with a clear clinical case definition. We observed wide variety in reference standards and study designs and now recommend consecutively designed studies. PMID:24829226

Physical Activity, Sedentary Behavior, Cardiorespiratory Fitness and Metabolic Syndrome in Adolescents: Systematic Review and Meta-Analysis of Observational Evidence

PubMed Central

2016-01-01

Background Metabolic syndrome (MetS) has been diagnosed in adolescents and among the associated factors are low levels of physical activity, sedentary behavior over long periods and low cardiorespiratory fitness. However, specifically in adolescents, studies present conflicting results. The aim of the present study was to conduct a systematic review and meta-analysis of observational studies, in order to map the association between physical activity, sedentary behavior, cardiorespiratory fitness and MetS in adolescents. Methods A search was performed in the databases PubMed, SPORTDiscus, LILACS and the Cochrane Library. For the meta-analysis, the odds ratio (OR) was calculated together with the respective confidence intervals (95% CI), in which the measures of effect were analyzed by dichotomous data (exposure variables) with MetS used as events. Results Eighteen studies were included in the meta-analysis. Primary analysis demonstrated that low levels of physical activity (OR = 1.35 [1.03 to 1.79]; p = 0.03) and low cardiorespiratory fitness (OR = 4.05 [2.09 to 7.87]; p < 0.01) were significantly associated with the development of MetS, while for sedentary behavior, represented by screen time > 2 hours/day, a significant association was not identified (OR = 1.20 [0.91 to 1.59]; p = 0.20). Subgroup analyses demonstrated that the association between low physical activity and MetS was dependent on the use of the accelerometry technique (OR = 2.93 [1.56 to 5.47]; p < 0.01). Screen time > 2 hours/day was significantly associated with MetS only on weekends (OR = 2.05 [1.13 to 3.73]; p = 0.02). With respect to cardiorespiratory fitness, a significant association with MetS was found independent of the maximal oxygen uptake (VO2max) measurement method. Conclusions Low levels of physical activity, low indices of cardiorespiratory fitness and sedentary behavior, represented by screen time > 2 hours/day on weekends, were significantly associated with the development of MetS in adolescence. PMID:27997601

Associations of Low Muscle Mass and the Metabolic Syndrome in Caucasian and Asian Middle-aged and Older Adults.

PubMed

Scott, D; Park, M S; Kim, T N; Ryu, J Y; Hong, H C; Yoo, H J; Baik, S H; Jones, G; Choi, K M

2016-03-01

Age-related declines in skeletal muscle mass may confer significant metabolic consequences for older adults. Associations of low muscle mass and metabolic syndrome (MetS) in Caucasians, and comparisons with associations observed in Asian populations, have not been reported. We examined associations of low muscle mass and metabolic syndrome (MetS) in Asian and Caucasian middle-aged and older men and women using criteria for low muscle mass. Two population-based studies of Australian (Tasmanian Older Adult Cohort Study; TASOAC; N=1005) and Korean (Korean Sarcopenic Obesity Study; KSOS; N=376) community-dwelling adults, mean age 62 and 58 years, respectively. Appendicular lean mass (aLM) determined by dual-energy X-ray absorptiometry and normalised to height squared (aLM/Ht2), weight (aLM/Wt) or body mass index (aLM/BMI). Participants in the lowest sex-specific 20% for aLM measures were defined as having low muscle mass. MetS was defined according to National Cholesterol Education Program Adult Treatment Panel III criteria. Although Australians demonstrated generally unfavourable anthropometric and metabolic characteristics compared to Koreans, prevalence of MetS was similar (29.5% in Australians and 31.4% in Koreans, respectively). Low aLM/Ht2 was associated with significantly reduced likelihood of MetS in both Australians (OR: 0.30, 95% CI 0.19 - 0.46) and Koreans (OR: 0.31, 95% CI 0.16 - 0.62). Conversely, low aLM/BMI was associated with increased odds for MetS in Australians (OR: 1.78, 95% CI 1.12 - 2.84), but not Koreans (OR: 1.33, 95% CI = 0.67 - 2.64). Low aLM/BMI is associated with significantly increased likelihood of MetS in Australian adults, but not Koreans, suggesting potential differences in effects of low muscle mass relative to body mass on cardiometabolic health in Caucasian and Asian middle-aged and older adults. Low muscle mass relative to height is associated with reduced likelihood of MetS in both populations.

Identifying cardiovascular disease risk and outcome: use of the plasma triglyceride/high-density lipoprotein cholesterol concentration ratio versus metabolic syndrome criteria.

PubMed

Salazar, M R; Carbajal, H A; Espeche, W G; Aizpurúa, M; Leiva Sisnieguez, C E; March, C E; Balbín, E; Stavile, R N; Reaven, G M

2013-06-01

Metabolic syndrome (MetS) has been shown to predict both risk and CVD events. We have identified sex-specific values for the triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio associated with an unfavourable cardio-metabolic risk profile, but it is not known whether it also predicts CVD outcome. To quantify risk for CVD outcomes associated with a high TG/HDL-C ratio and to compare this risk with that predicted using MetS, a population longitudinal prospective observational study was performed in Rauch City, Buenos Aires, Argentina. In 2003 surveys were performed on a population random sample of 926 inhabitants. In 2012, 527 women and 269 men were surveyed again in search of new CVD events. The first CVD event was the primary endpoint. Relative risks for CVD events between individuals above and below the TG/HDL-C cut-points, and with or without MetS, were estimated using Cox proportional hazard. The first CVD event was the primary endpoint. Relative risks for CVD events between individuals above and below the TG/HDL-C cut-points, and with or without MetS, were estimated using Cox proportional hazard. The number of subjects deemed at 'high' CVD risk on the basis of an elevated TG/HDL-C ratio (30%) or having the MetS (35%) was relatively comparable. The unadjusted hazard risk was significantly increased when comparing 'high' versus 'low' risk groups no matter which criteria was used, although it was somewhat higher in those with the MetS (HR = 3.17, 95% CI:1.79-5.60 vs. 2.16, 95% CI:1.24-3.75). However, this difference essentially disappeared when adjusted for sex and age (HR = 2.09, 95% CI:1.18-3.72 vs. 2.01, 95% CI:1.14-3.50 for MetS and TG/HDL-C respectively). An elevated TG/HDL-C ratio appears to be just as effective as the MetS diagnosis in predicting the development of CVD. © 2013 The Association for the Publication of the Journal of Internal Medicine.

Alternatives to Traditional EMS Dispatch and Transport: A Scoping Review of Reported Outcomes.

PubMed

Jensen, Jan L; Carter, Alix J E; Rose, Jennifer; Visintini, Sarah; Bourdon, Emmanuelle; Brown, Ryan; McVey, Jennifer; Travers, Andrew H

2015-09-01

Emergency medical services (EMS) programs, which provide an alternative to traditional EMS dispatch or transport to the emergency department (ED), are becoming widely implemented. This scoping review identified and catalogued all outcomes used to measure such alternative EMS programs. Data Source Broad systematized bibliographic and grey literature searches were conducted. Study Selection Inclusion criteria were 911 callers/EMS patients, reported on alternatives to traditional EMS dispatch OR traditional EMS transport to the ED, and reported an outcome measure. Data Extraction The reports were categorized as either alternative to dispatch or to EMS transport, and outcome measures were categorized and described. Data Synthesis The bibliographic search retrieved 13,215 records, of which 34 articles met the inclusion criteria, with an additional 10 added from reference list hand-searching (n=44 included). In the grey literature search, 31 websites were identified, from which four met criteria and were retrieved (n=4 included). Fifteen reports (16 studies) described alternatives to EMS dispatch, and 33 reports described alternatives to EMS transport. The most common outcomes reported in the alternatives to EMS dispatch reports were service utilization and decision accuracy. Twenty-four different specific outcomes were reported. The most common outcomes reported in the alternatives to EMS transport reports were service utilization and safety, and 50 different specific outcomes were reported. Numerous outcome measures were identified in reports of alternative EMS programs, which were catalogued and described. Researchers and program leaders should achieve consensus on uniform outcome measures, to allow benchmarking and improve comparison across programs.

Using the Center for Epidemiologic Studies Depression Scale to Screen for Depression in Systemic Lupus Erythematosus

PubMed Central

Julian, Laura J.; Gregorich, Steven E.; Tonner, Chris; Yazdany, Jinoos; Trupin, Laura; Criswell, Lindsey A.; Yelin, ED; Katz, Patricia P.

2013-01-01

Objective Identifying persons with systemic lupus erythematosus (SLE) at risk for depression would facilitate the identification and treatment of an important comorbidity conferring additional risk for poor outcomes. The purpose of this study was to determine the utility of a brief screening measure, the Center for Epidemiologic Studies Depression Scale (CES-D), in detecting mood disorders in persons with SLE. Methods This cross-sectional study examined 150 persons with SLE. Screening cut points were empirically derived using threshold selection methods, and receiver operating characteristic curves were estimated. The empirically derived cut points of the CES-D were used as the screening measures and were compared to other commonly used CES-D cut points in addition to other commonly used methods to screen for depression. Diagnoses of major depressive disorder or other mood disorders were determined using a “gold standard” structured clinical interview. Results Of the 150 persons with SLE, 26% of subjects met criteria for any mood disorder and 17% met criteria for major depressive disorder. Optimal threshold estimations suggested a CES-D cut score of 24 and above, which yielded adequate sensitivity and specificity in detecting major depressive disorder (88% and 93%, respectively) and correctly classified 92% of participants. To detect the presence of any mood disorder, a cut score of 20 and above was suggested, yielding sensitivity and specificity of 87% and correctly classifying 87%. Conclusion These results suggest the CES-D may be a useful screening measure to identify patients at risk for depression. PMID:21312347

Listening for Recollection: A Multi-Voxel Pattern Analysis of Recognition Memory Retrieval Strategies

PubMed Central

Quamme, Joel R.; Weiss, David J.; Norman, Kenneth A.

2010-01-01

Recent studies of recognition memory indicate that subjects can strategically vary how much they rely on recollection of specific details vs. feelings of familiarity when making recognition judgments. One possible explanation of these results is that subjects can establish an internally directed attentional state (“listening for recollection”) that enhances retrieval of studied details; fluctuations in this attentional state over time should be associated with fluctuations in subjects’ recognition behavior. In this study, we used multi-voxel pattern analysis of fMRI data to identify brain regions that are involved in listening for recollection. We looked for brain regions that met the following criteria: (1) Distinct neural patterns should be present when subjects are instructed to rely on recollection vs. familiarity, and (2) fluctuations in these neural patterns should be related to recognition behavior in the manner predicted by dual-process theories of recognition: Specifically, the presence of the recollection pattern during the pre-stimulus interval (indicating that subjects are “listening for recollection” at that moment) should be associated with a selective decrease in false alarms to related lures. We found that pre-stimulus activity in the right supramarginal gyrus met all of these criteria, suggesting that this region proactively establishes an internally directed attentional state that fosters recollection. We also found other regions (e.g., left middle temporal gyrus) where the pattern of neural activity was related to subjects’ responding to related lures after stimulus onset (but not before), suggesting that these regions implement processes that are engaged in a reactive fashion to boost recollection. PMID:20740073

Prevalence and healthcare actions of women in a large health system with a family history meeting the 2005 USPSTF recommendation for BRCA genetic counseling referral.

PubMed

Bellcross, Cecelia A; Leadbetter, Steven; Alford, Sharon Hensley; Peipins, Lucy A

2013-04-01

In 2005, the United States Preventive Services Task Force (USPSTF) released guidelines which outlined specific family history patterns associated with an increased risk for BRCA1/2 mutations, and recommended at-risk individuals be referred for genetic counseling and evaluation for BRCA testing. The purpose of this study was to assess the prevalence of individuals with a USPSTF increased-risk family history pattern, the frequency with which specific patterns were met, and resulting healthcare actions among women from the Henry Ford Health System. As part of a study evaluating ovarian cancer risk perception and screening, 2,524 randomly selected participants completed a detailed interview (response rate 76%) from an initial eligible cohort of 16,720 women. Approximately 6% of participants had a family history fulfilling one or more of the USPSTF patterns. Although 90% of these women had shared their family history with their provider, less than 20% had been referred for genetic counseling and only 8% had undergone genetic testing. Caucasian women with higher income and education levels were more likely to receive referrals. Among the 95 participants in the total study cohort who reported BRCA testing, 78% did not have a family history that met one of the USPSTF patterns. These results suggest a higher prevalence of women with an increased-risk family history than originally predicted by the USPSTF, and lack of provider recognition and referral for genetic services. Improvements in healthcare infrastructure and clinician education will be required to realize population level benefits from BRCA genetic counseling and testing.

Genotype-phenotype correlation in FMF patients: A "non classic" recessive autosomal or "atypical" dominant autosomal inheritance?

PubMed

Procopio, V; Manti, S; Bianco, G; Conti, G; Romeo, A; Maimone, F; Arrigo, T; Cutrupi, M C; Salpietro, C; Cuppari, C

2018-01-30

Uncertainty remains on the pathogenetic mechanisms, model of inheritance as well as genotype-phenotype correlation of FMF disease. To investigate the impact of genetic factors on the FMF phenotype and the disease inheritance model. A total of 107 FMF patients were enrolled. Patients were diagnosed clinically. All patients underwent genetic analysis of the FMF locus on 16p13.3. 9 distinct mutations were detected. Specifically, the 85.98% of patients showed a heterozygous genotype. The most common genotypes were p.Met680Ile/wt and p.Met694Val/wt. The most frequent clinical findings were fever, abdominal pain, joint pain, thoracic pain, and erysipelas-like erythema. Analysis of clinical data did not detect any significant difference in clinical phenotype among heterozygous, homozygous as well as compound homozygous subjects, further supporting the evidence that, contrary to the recessive autosomal inheritance, heterozygous patients fulfilled the criteria of clinical FMF. Moreover, subjects with p.Met694Val/wt and p.Met680Ile/wt genotype reported the most severe clinical phenotype. p.Ala744Ser/wt, p.Glu148Gln/Met680Ile, p.Met680Ile/Met680Ile, p.Met680Ile/Met694Val, p.Pro369Ser/wt, p.Met694Ile/wt, p.Glu148Gln/Glu148Gln, p.Lys695Arg/wt resulted in 100% pathogenicity. The existence of a "non classic" autosomal recessive inheritance as well as of an "atypical" dominant autosomal inheritance with incomplete penetrance and variable expressivity cannot be excluded in FMF. Copyright © 2017 Elsevier B.V. All rights reserved.

Enhanced MET Translation and Signaling Sustains K-Ras-Driven Proliferation under Anchorage-Independent Growth Conditions.

PubMed

Fujita-Sato, Saori; Galeas, Jacqueline; Truitt, Morgan; Pitt, Cameron; Urisman, Anatoly; Bandyopadhyay, Sourav; Ruggero, Davide; McCormick, Frank

2015-07-15

Oncogenic K-Ras mutation occurs frequently in several types of cancers, including pancreatic and lung cancers. Tumors with K-Ras mutation are resistant to chemotherapeutic drugs as well as molecular targeting agents. Although numerous approaches are ongoing to find effective ways to treat these tumors, there are still no effective therapies for K-Ras mutant cancer patients. Here we report that K-Ras mutant cancers are more dependent on K-Ras in anchorage-independent culture conditions than in monolayer culture conditions. In seeking to determine mechanisms that contribute to the K-Ras dependency in anchorage-independent culture conditions, we discovered the involvement of Met in K-Ras-dependent, anchorage-independent cell growth. The Met signaling pathway is enhanced and plays an indispensable role in anchorage-independent growth even in cells in which Met is not amplified. Indeed, Met expression is elevated under anchorage-independent growth conditions and is regulated by K-Ras in a MAPK/ERK kinase (MEK)-dependent manner. Remarkably, in spite of a global downregulation of mRNA translation during anchorage-independent growth, we find that Met mRNA translation is specifically enhanced under these conditions. Importantly, ectopic expression of an active Met mutant rescues K-Ras ablation-derived growth suppression, indicating that K-Ras-mediated Met expression drives "K-Ras addiction" in anchorage-independent conditions. Our results indicate that enhanced Met expression and signaling is essential for anchorage-independent growth of K-Ras mutant cancer cells and suggests that pharmacological inhibitors of Met could be effective for K-Ras mutant tumor patients. ©2015 American Association for Cancer Research.

Structured lifestyle intervention in patients with the metabolic syndrome mitigates oxidative stress but fails to improve measures of cardiovascular autonomic neuropathy.

PubMed

Pennathur, Subramaniam; Jaiswal, Mamta; Vivekanandan-Giri, Anuradha; White, Elizabeth A; Ang, Lynn; Raffel, David M; Rubenfire, Melvyn; Pop-Busui, Rodica

2017-09-01

To assess the role of oxidative stress in mediating adverse outcomes in metabolic syndrome (MetS) and resultant cardiovascular autonomic neuropathy (CAN), and to evaluate the effects of lifestyle interventions on measures of oxidative stress and CAN in subjects with MetS. Pilot study in 25 non-diabetic subjects with MetS (age 49±10years, 76% females) participating in a 24-week lifestyle intervention (supervised aerobic exercise/Mediterranean diet), and 25 age-matched healthy controls. CAN was assessed by cardiovascular reflex tests, heart rate variability (HRV) and PET imaging with sympathetic analog [ 11 C] meta-hydroxyephedrine ([ 11 C]HED). Specific oxidative fingerprints were measured by liquid-chromatography/mass-spectrometry (LC/MS). At baseline, MetS subjects had significantly higher oxidative stress markers [3-nitrotyrosine (234±158 vs. 54±47μmol/mol tyrosine), ortho-tyrosine (59±38 vs. 18±10μmol/molphenylalanine, all P<0.0001], and impaired HRV at rest and during deep breathing (P=0.039 and P=0.021 respectively) compared to controls. Twenty-four-week lifestyle intervention significantly reduced all oxidative stress markers (all P<0.01) but did not change any of the CAN measures. Subjects with MetS present with signs of CAN and increased oxidative stress in the absence of diabetes. The 24-week lifestyle intervention was effective in ameliorating oxidative stress, but did not improve measures of CAN. Larger clinical trials with longer duration are required to confirm these findings. Copyright © 2017 Elsevier Inc. All rights reserved.

A dietary pattern including nopal, chia seed, soy protein, and oat reduces serum triglycerides and glucose intolerance in patients with metabolic syndrome.

PubMed

Guevara-Cruz, Martha; Tovar, Armando R; Aguilar-Salinas, Carlos A; Medina-Vera, Isabel; Gil-Zenteno, Lidia; Hernández-Viveros, Isaac; López-Romero, Patricia; Ordaz-Nava, Guillermo; Canizales-Quinteros, Samuel; Guillen Pineda, Luz E; Torres, Nimbe

2012-01-01

Metabolic syndrome (MetS) is a health problem throughout the world and is associated with cardiovascular disease and diabetes. Thus, the purpose of the present work was to evaluate the effects of a dietary pattern (DP; soy protein, nopal, chia seed, and oat) on the biochemical variables of MetS, the AUC for glucose and insulin, glucose intolerance (GI), the relationship of the presence of certain polymorphisms related to MetS, and the response to the DP. In this randomized trial, the participants consumed their habitual diet but reduced by 500 kcal for 2 wk. They were then assigned to the placebo (P; n = 35) or DP (n = 32) group and consumed the reduced energy diet plus the P or DP beverage (235 kcal) minus the energy provided by these for 2 mo. All participants had decreases in body weight (BW), BMI, and waist circumference during the 2-mo treatment (P < 0.0001); however, only the DP group had decreases in serum TG, C-reactive protein (CRP), and AUC for insulin and GI after a glucose tolerance test. Interestingly, participants in the DP group with MetS and the ABCA1 R230C variant had a greater decrease in BW and an increase in serum adiponectin concentration after 2 mo of dietary treatment than those with the ABCA1 R230R variant. The results from this study suggest that lifestyle interventions involving specific DP for the treatment of MetS could be more effective if local foods and genetic variations of the population are considered.

Enhanced MET translation and signaling sustains K-Ras driven proliferation under anchorage-independent growth conditions

PubMed Central

Fujita-Sato, Saori; Galeas, Jacqueline; Truitt, Morgan; Pitt, Cameron; Urisman, Anatoly; Bandyopadhyay, Sourav; Ruggero, Davide; McCormick, Frank

2015-01-01

Oncogenic K-Ras mutation occurs frequently in several types of cancers including pancreatic and lung cancers. Tumors with K-Ras mutation are resistant to chemotherapeutic drugs as well as molecular targeting agents. Although numerous approaches are ongoing to find effective ways to treat these tumors, there are still no effective therapies for K-Ras mutant cancer patients. Here we report that K-Ras mutant cancers are more dependent on K-Ras in anchorage independent culture conditions than in monolayer culture conditions. In seeking to determine mechanisms that contribute to the K-Ras dependency in anchorage independent culture conditions, we discovered the involvement of Met in K-Ras-dependent, anchorage independent cell growth. The Met signaling pathway is enhanced and plays an indispensable role in anchorage independent growth even in cells in which Met is not amplified. Indeed, Met expression is elevated under anchorage-independent growth conditions and is regulated by K-Ras in a MAPK/ERK kinase (MEK)-dependent manner. Remarkably, in spite of a global down-regulation of mRNA translation during anchorage independent growth, we find that Met mRNA translation is specifically enhanced under these conditions. Importantly, ectopic expression of an active Met mutant rescues K-Ras ablation-derived growth suppression, indicating that K-Ras mediated Met expression drives “K-Ras addiction” in anchorage independent conditions. Our results indicate that enhanced Met expression and signaling is essential for anchorage independent growth of K-Ras mutant cancer cells and suggests that pharmacological inhibitors of Met could be effective for K-Ras mutant tumor patients. PMID:25977330

Dynamic gene and protein expression patterns of the autism-associated met receptor tyrosine kinase in the developing mouse forebrain.

PubMed

Judson, Matthew C; Bergman, Mica Y; Campbell, Daniel B; Eagleson, Kathie L; Levitt, Pat

2009-04-10

The establishment of appropriate neural circuitry depends on the coordination of multiple developmental events across space and time. These events include proliferation, migration, differentiation, and survival-all of which can be mediated by hepatocyte growth factor (HGF) signaling through the Met receptor tyrosine kinase. We previously found a functional promoter variant of the MET gene to be associated with autism spectrum disorder, suggesting that forebrain circuits governing social and emotional function may be especially vulnerable to developmental disruptions in HGF/Met signaling. However, little is known about the spatiotemporal distribution of Met expression in the forebrain during the development of such circuits. To advance our understanding of the neurodevelopmental influences of Met activation, we employed complementary Western blotting, in situ hybridization, and immunohistochemistry to comprehensively map Met transcript and protein expression throughout perinatal and postnatal development of the mouse forebrain. Our studies reveal complex and dynamic spatiotemporal patterns of expression during this period. Spatially, Met transcript is localized primarily to specific populations of projection neurons within the neocortex and in structures of the limbic system, including the amygdala, hippocampus, and septum. Met protein appears to be principally located in axon tracts. Temporally, peak expression of transcript and protein occurs during the second postnatal week. This period is characterized by extensive neurite outgrowth and synaptogenesis, supporting a role for the receptor in these processes. Collectively, these data suggest that Met signaling may be necessary for the appropriate wiring of forebrain circuits, with particular relevance to the social and emotional dimensions of behavior. (c) 2009 Wiley-Liss, Inc.

Mediating effects of dietary intake on associations of TV viewing, body mass index and metabolic syndrome in adolescents

PubMed Central

McNaughton, S. A.; Lacy, K. E.; Dunstan, D. W.; Carson, V.; Salmon, J.

2016-01-01

Summary Objective Evidence suggests that TV viewing is associated with body mass index (BMI) and metabolic syndrome (MetS) in adolescents. However, it is unclear whether dietary intake mediates these relationships. Methods A cross‐sectional analysis was conducted in adolescents (12–19 years) participating in the 2003–2006 United States National Health and Nutrition Examination Survey. BMI z scores (zBMI) (n = 3,161) and MetS (n = 1,379) were calculated using age‐ and sex‐specific criteria for adolescents. TV viewing (h/day) was measured via a self‐reported questionnaire, and dietary intake was assessed using two 24‐h recalls. Using the MacKinnon method, a series of mediation analyses were conducted examining five dietary mediators (total energy intake, fruit and vegetable intake, discretionary snacks, sugar‐sweetened beverages and diet quality) of the relationships between TV viewing and zBMI and MetS. Results Small positive relationships were observed between TV viewing and zBMI (β = 0.99, p < 0.001) and TV viewing and MetS (OR = 1.18, p = 0.046). No dietary element appeared to mediate the relationship between TV viewing and zBMI. However, sugar‐sweetened beverage consumption and fruit and vegetable intake partially mediated the relationship between TV viewing and MetS, explaining 8.7% and 4.1% of the relationship, respectively. Conclusions These findings highlight the complexity of the relationships between TV viewing, dietary intake and cardiometabolic health outcomes, and that TV viewing should remain a target for interventions. PMID:27708839

Mediating effects of dietary intake on associations of TV viewing, body mass index and metabolic syndrome in adolescents.

PubMed

Fletcher, E A; McNaughton, S A; Lacy, K E; Dunstan, D W; Carson, V; Salmon, J

2016-09-01

Evidence suggests that TV viewing is associated with body mass index (BMI) and metabolic syndrome (MetS) in adolescents. However, it is unclear whether dietary intake mediates these relationships. A cross-sectional analysis was conducted in adolescents (12-19 years) participating in the 2003-2006 United States National Health and Nutrition Examination Survey. BMI z scores (zBMI) ( n  = 3,161) and MetS ( n  = 1,379) were calculated using age- and sex-specific criteria for adolescents. TV viewing (h/day) was measured via a self-reported questionnaire, and dietary intake was assessed using two 24-h recalls. Using the MacKinnon method, a series of mediation analyses were conducted examining five dietary mediators (total energy intake, fruit and vegetable intake, discretionary snacks, sugar-sweetened beverages and diet quality) of the relationships between TV viewing and zBMI and MetS. Small positive relationships were observed between TV viewing and zBMI (β = 0.99, p  < 0.001) and TV viewing and MetS (OR = 1.18, p  = 0.046). No dietary element appeared to mediate the relationship between TV viewing and zBMI. However, sugar-sweetened beverage consumption and fruit and vegetable intake partially mediated the relationship between TV viewing and MetS, explaining 8.7% and 4.1% of the relationship, respectively. These findings highlight the complexity of the relationships between TV viewing, dietary intake and cardiometabolic health outcomes, and that TV viewing should remain a target for interventions.

Efficacy of neck circumference to identify metabolic syndrome in 3-10 year-old European children: Results from IDEFICS study.

PubMed

Formisano, A; Bammann, K; Fraterman, A; Hadjigeorgiou, C; Herrmann, D; Iacoviello, L; Marild, S; Moreno, L A; Nagy, P; Van Den Bussche, K; Veidebaum, T; Lauria, F; Siani, A

2016-06-01

Several studies demonstrated that larger neck circumference (NC) in children and adolescents may help to identify obesity and cardio-metabolic abnormalities. We aimed to evaluate the correlation between NC and metabolic syndrome (MetS) risk factors and to determine the utility of this anthropometric index to identify MetS in European children. The present cross-sectional analysis includes 15,673 children (3-10 years) participating in the IDEFICS study. A continuous MetS (cMetS) score was calculated summing age and sex standardized z-scores of specific MetS risk factors. Receiver Operating Characteristic analysis, stratified by one-year age groups, was used to determine the ability of NC to identify children with unfavorable metabolic profile, corresponding to cMetS score ≥ 90th percentile. The areas under the curve values for NC associated with cMetS score values ≥ 90th percentile were significantly greater in girls than in boys (p < 0.001), except for 5 < 6 years group. For boys, optimal NC cut-off values ranged from 26.2 cm for the lowest age group (3 < 4 years), up to 30.9 cm for the highest age group (9 < 10 years). In girls, corresponding values varied from 24.9 cm to 29.6 cm. The study demonstrated the efficacy of NC in identifying European children with an unfavorable metabolic profile. Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Circulation as Assessment: Collection Development Policies Evaluated in Terms of Circulation at a Small Academic Library.

ERIC Educational Resources Information Center

Dinkins, Debbi

2003-01-01

Discusses the use of academic library circulation statistics to assess whether user needs are being met and describes a study at Stetson University that investigated collection development practices by comparing circulation statistics for books selected by faculty in support of departmental curricula with those of librarian selections. (Author/LRW)

In vivo detection of c-MET expression in a rat hepatocarcinogenesis model using molecularly targeted magnetic resonance imaging.

PubMed

Towner, Rheal A; Smith, Nataliya; Tesiram, Yasvir A; Abbott, Andrew; Saunders, Debbie; Blindauer, Rebecca; Herlea, Oana; Silasi-Mansat, Robert; Lupu, Florea

2007-01-01

The multifunctional growth factor scatter factor/hepatocyte growth factor and its tyrosine kinase receptor, c-MET, have been implicated in the genesis and malignant progression of numerous human malignancies, including hepatocellular carcinomas. The incidence of hepatocellular carcinomas in the United States has increased noticeably over the past two decades and is listed as the fifth major cancer in men worldwide. In this study, we used a choline-deficient l-amino acid (CDAA)-defined rat hepatocarcinogenesis model to visualize increased in vivo expression of the c-MET antigen in neoplastic lesion formation with the use of a super paramagnetic iron oxide (SPIO)-anti-c-MET molecularly targeted magnetic resonance imaging (MRI) contrast agent. SPIO-anti-c-MET was used for the first time to detect overexpression of c-MET in neoplastic nodules and tumors within the livers of CDAA-treated rats, as determined by a decrease in MRI signal intensity and a decrease in regional T(2) values. Specificity for the binding of the molecularly targeted anti-c-MET contrast agent was determined using rat hepatoma (H4-II-E-C3) cell cultures and immunofluorescence microscopic imaging of the targeting agents within neoplastic liver tissue 1 to 2 hours following intravenous administration of SPIO-anti-c-MET and MRI investigation. This method has the ability to visualize in vivo the overexpression of c-MET at early developmental stages of tumor formation.

Genomic profiling of a Hepatocyte growth factor-dependent signature for MET-targeted therapy in glioblastoma.

PubMed

Johnson, Jennifer; Ascierto, Maria Libera; Mittal, Sandeep; Newsome, David; Kang, Liang; Briggs, Michael; Tanner, Kirk; Marincola, Francesco M; Berens, Michael E; Vande Woude, George F; Xie, Qian

2015-09-17

Constitutive MET signaling promotes invasiveness in most primary and recurrent GBM. However, deployment of available MET-targeting agents is confounded by lack of effective biomarkers for selecting suitable patients for treatment. Because endogenous HGF overexpression often causes autocrine MET activation, and also indicates sensitivity to MET inhibitors, we investigated whether it drives the expression of distinct genes which could serve as a signature indicating vulnerability to MET-targeted therapy in GBM. Interrogation of genomic data from TCGA GBM (Student's t test, GBM patients with high and low HGF expression, p ≤ 0.00001) referenced against patient-derived xenograft (PDX) models (Student's t test, sensitive vs. insensitive models, p ≤ 0.005) was used to identify the HGF-dependent signature. Genomic analysis of GBM xenograft models using both human and mouse gene expression microarrays (Student's t test, treated vs. vehicle tumors, p ≤ 0.01) were performed to elucidate the tumor and microenvironment cross talk. A PDX model with EGFR(amp) was tested for MET activation as a mechanism of erlotinib resistance. We identified a group of 20 genes highly associated with HGF overexpression in GBM and were up- or down-regulated only in tumors sensitive to MET inhibitor. The MET inhibitors regulate tumor (human) and host (mouse) cells within the tumor via distinct molecular processes, but overall impede tumor growth by inhibiting cell cycle progression. EGFR (amp) tumors undergo erlotinib resistance responded to a combination of MET and EGFR inhibitors. Combining TCGA primary tumor datasets (human) and xenograft tumor model datasets (human tumor grown in mice) using therapeutic efficacy as an endpoint may serve as a useful approach to discover and develop molecular signatures as therapeutic biomarkers for targeted therapy. The HGF dependent signature may serve as a candidate predictive signature for patient enrollment in clinical trials using MET inhibitors. Human and mouse microarrays maybe used to dissect the tumor-host interactions. Targeting MET in EGFR (amp) GBM may delay the acquired resistance developed during treatment with erlotinib.

Accuracy of detection of carboxyhemoglobin and methemoglobin in human and bovine blood with an inexpensive, pocket-size infrared scanner.

PubMed

Bickler, Margot P; Rhodes, Laura J

2018-01-01

Detecting life-threatening common dyshemoglobins such as carboxyhemoglobin (COHb, resulting from carbon monoxide poisoning) or methemoglobin (MetHb, caused by exposure to nitrates) typically requires a laboratory CO-oximeter. Because of cost, these spectrophotometer-based instrument are often inaccessible in resource-poor settings. The aim of this study was to determine if an inexpensive pocket infrared spectrometer and smartphone (SCiO®Pocket Molecular Sensor, Consumer Physics Ltd., Israel) accurately detects COHb and MetHb in single drops of blood. COHb was created by adding carbon monoxide gas to syringes of heparinized blood human or cow blood. In separate syringes, MetHb was produced by addition of sodium nitrite solution. After incubation and mixing, fractional concentrations of COHb or MetHb were measured using a Radiometer ABL-90 Flex® CO-oximeter. Fifty microliters of the sample were then placed on a microscope slide, a cover slip applied and scanned with the SCiO spectrometer. The spectrograms were used to create simple linear models predicting [COHb] or [MetHb] based on spectrogram maxima, minima and isobestic wavelengths. Our model predicted clinically significant carbon monoxide poisoning (COHb ≥15%) with a sensitivity of 93% and specificity of 88% (regression r2 = 0.63, slope P<0.0001), with a mean bias of 0.11% and an RMS error of 21%. Methemoglobinemia severe enough to cause symptoms (>20% MetHb) was detected with a sensitivity of 100% and specificity of 71% (regression r2 = 0.92, slope P<0.001) mean bias 2.7% and RMS error 21%. Although not as precise as a laboratory CO-oximeter, an inexpensive pocket-sized infrared scanner/smartphone detects >15% COHb or >20% MetHb on a single drop of blood with enough accuracy to be useful as an initial clinical screening. The SCiO and similar relatively low cost spectrometers could be developed as inexpensive diagnostic tools for developing countries.

Meeting physical activity recommendations: self-regulatory efficacy characterizes differential adherence during arthritis flares.

PubMed

Gyurcsik, Nancy C; Brawley, Lawrence R; Spink, Kevin S; Sessford, James D

2013-02-01

Using social-cognitive theory, we examined whether adults who experienced an arthritis flare and met/did not meet the disease-specific public health recommended dose for physical activity differed in their self-regulatory efficacy beliefs, overall pain, and flare-related factors. Adults with arthritis (N = 56; M(age) = 49.41 ± 11.56 years) participated in this prospective study. Multivariate analysis of variance comparing groups who met or did not meet the recommended dose (n(met) = 24, ≥ 150 minutes/week vs. n(not met) = 32, < 150 min/week) on efficacy, overall pain, and flare-related factors was significant (p < .01; η(partial)² = .28). People meeting the dose had significantly greater self-regulatory efficacy to overcome arthritis barriers (M(met dose) = 7.33 ± 1.95 vs. M(did not meet dose) = 5.74 ± 2.08, η(partial)² = .14) and to schedule/plan (M(met dose) = 7.27 ± 1.80 vs. M(did not meet dose) = 5.72 ± 1.90, η(partial)² = .15). Overall pain and flare-related factors did not differ (ps > .05). During flares, individuals with greater self-regulatory efficacy to manage disease barriers and plan their physical activity were more adherent to disease-specific public health activity recommendations. This study was the first to demonstrate differences in social cognitions that characterize adherence to recommended activity among people challenged by arthritis flares. Findings support the theoretical position that self-regulatory efficacy is related to better adherence in the face of challenging disease-related circumstances. The importance of studying individual characteristics of people who succeed in being active despite such obstacles is stressed.

Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment.

PubMed

Shi, Puyu; Oh, You-Take; Zhang, Guojing; Yao, Weilong; Yue, Ping; Li, Yikun; Kanteti, Rajani; Riehm, Jacob; Salgia, Ravi; Owonikoko, Taofeek K; Ramalingam, Suresh S; Chen, Mingwei; Sun, Shi-Yong

2016-10-01

The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs; e.g., AZD9291), which selectively and irreversibly inhibit EGFR activating and T790M mutants, represent very promising therapeutic options for patients with non-small cell lung cancer (NSCLC) that has become resistant to 1st generation EGFR-TKIs due to T790M mutation. However, eventual resistance to the 3rd generation EGFR-TKIs has already been described in the clinic, resulting in disease progression. Therefore, there is a great challenge and urgent need to understand how this resistance occurs and to develop effective strategies to delay or overcome the resistance. The current study has demonstrated that Met amplification and hyperactivation is a resistance mechanism to both 1st and 3rd generation EGFR-TKIs since both erlotinib- and AZD9291-resistant HCC827 cell lines possessed amplified Met gene and hyperactivated Met, and were cross-resistant to AZD9291 or erlotinib. Met inhibition overcame the resistance of these cell lines to AZD9291 both in vitro and in vivo, including enhancement of apoptosis or G1 cell cycle arrest. Hence, we suggest that Met inhibition is also an effective strategy to overcome resistance of certain EGFR-mutated NSCLCs with Met amplification to AZD9291, warranting the further clinical validation of our findings. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Structure Based Drug Design of Crizotinib (PF-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal-Epithelial Transition Factor (c-MET) Kinase and Anaplastic Lymphoma Kinase (ALK)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cui, J Jean; Tran-Dube,; #769

2011-08-03

Because of the critical roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6-dichlorophenyl group of 3 via a more direct vector and thus with amore » better ligand efficiency (LE). Further optimization of the lead series generated the clinical candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties.« less

Psychometric characteristics of single-word tests of children's speech sound production.

PubMed

Flipsen, Peter; Ogiela, Diane A

2015-04-01

Our understanding of test construction has improved since the now-classic review by McCauley and Swisher (1984). The current review article examines the psychometric characteristics of current single-word tests of speech sound production in an attempt to determine whether our tests have improved since then. It also provides a resource that clinicians may use to help them make test selection decisions for their particular client populations. Ten tests published since 1990 were reviewed to determine whether they met the 10 criteria set out by McCauley and Swisher (1984), as well as 7 additional criteria. All of the tests reviewed met at least 3 of McCauley and Swisher's (1984) original criteria, and 9 of 10 tests met at least 5 of them. Most of the tests met some of the additional criteria as well. The state of the art for single-word tests of speech sound production in children appears to have improved in the last 30 years. There remains, however, room for improvement.

Photochemical cleavage of metal--carbon nanocrystals and their reconstruction into met--cars clusters

NASA Astrophysics Data System (ADS)

Pilgrim, J. S.; Duncan, M. A.

1994-10-01

Titanium and zirconium metal--carbon clusters are produced by laser vaporization in a pulsed nozzle source and detected with time-of-flight mass spectrometry. In addition to the now-familiar "met-cars" stoichiometry (M8C12), larger magic number clusters are produced with near 1:1 metal--carbon ratios. The special stoichiometries observed correspond to face-centered cubic crystal fragments, with a strong preference for fragments with symmetrical x,y,z dimensions. Mass-selected photodissociation experiments are used to investigate the structural patterns and stabilities of these systems. Photodissociation of the larger "nanocrystal" clusters leads to cleavage along crystal planes, producing smaller crystals also having highly symmetric dimensions. Photoexcitation of all these crystallites, in particular the 3 × 3 × 3 species, also leads to surface reconstruction, forming the M8C12 met-cars cluster and/or the M8C13 cluster, the latter of which is assigned to a met--cars cage with an endohedral carbon atom.

Development and Evaluation of TiAl Sheet Structures for Hypersonic Applications

NASA Technical Reports Server (NTRS)

Draper, S. L.; Krause, D.; Lerch, B.; Locci, I. E.; Doehnert, B.; Nigam, R.; Das, G.; Sickles, P.; Tabernig, B.; Reger, N.;

Lesbian, gay, bisexual, and transgender parents seeking health care for their children: a systematic review of the literature.

PubMed

Shields, Linda; Zappia, Tess; Blackwood, Diana; Watkins, Rochelle; Wardrop, Joan; Chapman, Rose

2012-12-01

Few studies have examined the issues faced by lesbian, gay, bisexual, and transgender (LGBT)-parented families in relation to their access to and satisfaction with healthcare services for their children. It is thought that LGBT individuals have experienced negative interactions with the healthcare environment. To systematically review the literature investigating the experience of LGBT parents seeking health care for their children. A search of the following databases: Cochrane Library, CINAHL, Embase, Google Scholar, Medline, PsychInfo, Science Direct, Sociological Abstracts, Proquest, Scopus, and Web of Science was conducted. Using the PRISMA flow chart and processes of the United Kingdom Centre for Reviews and Dissemination, we selected and analysed relevant studies. Four studies that met the inclusion criteria were identified. Studies showed that while the experience of LGBT parents seeking health care was largely positive, strategies need to be implemented to improve the quality of healthcare services for LGBT families and ensure that their needs are met. Although many LGBT parents have positive experiences of health care, some still experience discrimination and prejudice. Specific educational interventions are needed to support LGBT parents seeking health care for their children. Further research is required to explore LGBT-parented families' experiences of healthcare services, and this should include children's experiences. © 2012 Sigma Theta Tau International.

A regenerative fuel cell system for modular space station integrated electrical power.

NASA Technical Reports Server (NTRS)

Wynveen, R. A.; Schubert, F. H.

1973-01-01

A regenerative fuel cell system (RFCS) for energy storage aboard the Modular Space Station (MSS) was selected over the battery technique because of lower cost, lower launch weight, lower required solar array area, and its ability to be integrated into the station's reaction control and environmental control and life support subsystems in addition to the electrical power subsystem. The total MSS energy storage requirement was met by dividing it into four equal modular RFCSs, each made up of a fuel cell subsystem, a water electrolysis subsystem, a gas accumulator subassembly, and a water tank subassembly. The weight of each of the four RFCSs varied from 4000 to 7000 lb with the latter being a more maintainable design. The specific energy ranged between 5.6 to 9.4 watt-hr/lb.

[Principles and Methods for Formulating National Standards of "Regulations of Acupuncture-nee- dle Manipulating techniques"].

PubMed

Gang, Wei-juan; Wang, Xin; Wang, Fang; Dong, Guo-feng; Wu, Xiao-dong

2015-08-01

The national standard of "Regulations of Acupuncture-needle Manipulating Techniques" is one of the national Criteria of Acupuncturology for which a total of 22 items have been already established. In the process of formulation, a series of common and specific problems have been met. In the present paper, the authors expound these problems from 3 aspects, namely principles for formulation, methods for formulating criteria, and considerations about some problems. The formulating principles include selection and regulations of principles for technique classification and technique-related key factors. The main methods for formulating criteria are 1) taking the literature as the theoretical foundation, 2) taking the clinical practice as the supporting evidence, and 3) taking the expounded suggestions or conclusions through peer review.